Pain Management Secrets

TABLE 32-1. A V A I L A B L E N O N P R E S C R I P T I O N ( O T C ) T O P I C E U T I C A L S Example Products Active Ingredient Use (Manufacturer) Salicylate-Containing Products Myoflex (Fisons) Many products Relief of pain of available, ranging muscular aches, neuralg Sportscreme from 83%-55% methyl rheumatism, arthritis, (Chattern) salicylate in creams, gels, sprains, and like ointments, and lotions conditions Infrarub (Whitehall) Aspercreme (Chattern) Arthritis Formula Bengay (Pfizer) Combination Products Many different Relief of pain of muscu Flexall Ultra Plus products that aches, neuralgia, Gel (Chattern) combine menthol rheumatism, arthritis, Icy Hot Chill Stick (Chattern) or camphor with a sprains, and like conditi Arthritis Hot salicylate or capsaicin Cream (Chattern) in creams, gels, liquids, or Banalg Lotion (Forest) patches

(CONTINUED) Common Side Additional Tips Information for Effects for Use Proper Use gia, Apply to affected If applied to Not recommended for use areas no more than large areas on mucous membranes 3 or 4 times per day may cause tinnitus, Avoid contact with Apply only to intact skin nausea, or eyes, mouth, or nose vomiting and inside of ears For external use only ular Apply to affected See Not recommended for use ions areas no more than information on mucous membranes 3 or 4 times per day above for each of the various Avoid contact with CHAPTER 32 TOPICEUTICALS 245 Apply only to intact skin ingredients’ eyes, mouth, or nose side effects and inside of ears For external use only

246 CHAPTER 32 TOPICEUTICALS Products that contain antiinflammatory ingredients, such as methyl salicylate (e.g., Myoflex or Aspercreme) work by reducing the inflammation (swelling) at the site of injury. By reducing the inflammation in the affected area, these compounds reduce the ongoing irritation of local nerves. In turn, this reduces the amount of pain signals these nerves send to the brain. A relatively new group of OTC topical analgesics are made from hot chili peppers. One of the chemicals contained within these peppers (capsaicin) is the main ingredient of products such as Zostrix and Capzasin-HP. They work to relieve pain by emptying the nerves of a chemical that is necessary for the nerve to send pain signals to the brain. Initially, as the medication empties the chemical from the nerve, there may be a temporary increase in pain; this usually subsides within a few minutes after application. These particular medications should be applied carefully, and patients should wash hands thoroughly after application to prevent a burning sensation caused by touching other areas of the body. Finally, certain OTC topical analgesic products may contain various combinations of the ingredients mentioned above in an attempt to gain added benefit by using together medications that work differently. 6. What are specific examples of OTC pain relievers? Examples of OTC pain relievers can be found in Table 32-1, which includes information about active ingredients, proper use, and side effects. PRESCRIPTION PAIN RELIEVERS 7. What are the most commonly prescribed topiceuticals in the United States? How are they used? Over the past 5 years, there has been increasing interest in developing topical medications for the treatment of various pain conditions. Table 32-2 lists prescription topiceuticals available in the United States and includes information concerning their use, directions for use, and side effects. Representative of this subcategory of topiceuticals are the Lidoderm patch and EMLA cream. In 1999, the Lidoderm patch (lidocaine 5%) (Endo Pharmaceuticals, Chadds Ford, Pa.) was approved by the Food and Drug Administration and introduced for the relief of pain caused by damaged nerves following a shingles infection. It works to block the formation and movement of pain signals from the injured or affected nerves to the brain. Damaged and affected peripheral sensory nerves are extremely sensitive to the blocking effects of lidocaine; therefore, absorption of the drug into the bloodstream is not necessary for effect. This topical formulation releases an amount of lidocaine sufficient to block pain signals in the local tissues but not enough to cause complete numbness of the area. It reduces pain but does not affect other sensations. Lidoderm is a 10-by-14-cm, white, polyester felt patch that contains an adhesive with 5% lidocaine (700 mg) and is covered with a clear, film-release liner. The liner is removed prior to patch application to the most painful area of intact skin (e.g., no blisters or open skin ulcers). It also can act as a barrier for patients whose painful area may be extra sensitive to touch. Since the Lidoderm patch’s introduction, it has been also widely used successfully for pain associated with other nerves, such as diabetic neuropathy, carpel tunnel syndrome, and postmastectomy pain, as well as nonnerve pains such as low back, myofascial, osteoarthritis, and sports injury pains. EMLA cream (AstraZeneca Pharmaceuticals, Wilmington, Del.) is a cream or a topical adhesive disc system that delivers medications (lidocaine and procaine) for the production of complete skin numbness in the area to which it is applied. This medication is used in newborns, children, and adults and can be applied to normal intact skin for relief of local pain resulting from needle sticks for blood draws and needle insertion into veins and mucous membranes in advance of superficial minor surgery (e.g., circumcision or genital wart removal) or skin procedures (e.g., tattoo removal, biopsies, and laser treatments). Lidocaine and procaine work

TABLE 32-2. A V A I L A B L E P R E S C R I P T I O N T O P I C E U T I C A L S Formulation Use Infor Prop Lidoderm Lidocaine 5% Relief of pain Patch (lidocaine in a nonwoven, persisting after a Appl patch 5%) polyester shingles infection patch felt patch remo Endo Pharmaceuticals prote (Chadds to th Ford, Pa.) for 1 in a 2 Appl intac Cut t fit th Synera Topical Lidocaine 70 mg Relief of local pain For n Patch (lidocaine and tetracaine 70 caused by needle or ve 70 mg and mg in a patch insertion into veins, patch tetracaine 70 mg) containing a needle sticks for minu heating element blood draws, or skin Endo procedures of the For s Pharmaceuticals upper skin layers invol (Chadds Ford, Pa.) (e.g., biopsy of the layer skin where tissue is patch removed for further prior examination) Appl intac

rmation for Common Side Effects Additional Tips for Use per Use Mild redness or Avoid contact with eyes ly up to 3 swelling of skin in area Fold the patch onto itself hes (after of patch application; and discard in trash; keep oving the generally clears up away from children and pets ective liner) after patch removal Store in envelopes until use he site of pain so the patches do not 12 hours dry out 24 hour period Do not apply in conjunction with other creams, ly only to dry, ointments, lotions, or heating ct skin pads the patch if needed to he area of painful skin needle insertion Mild redness, swelling, Do not cut the CHAPTER 32 TOPICEUTICALS 247 ein puncture, apply 1 paleness of skin, or patch or remove h for 20 to 30 abnormal feeling in the top cover—the patch utes area of patch could heat to temperatures application; generally that could cause burns skin procedures clears up after patch lving the upper removal Do not block the rs of the skin, apply holes on the top h for 30 minutes Remove patch if of the patch—the patch may r to the procedure irritation or burning not properly heat sensation occurs with ly only to patch application Fold the patch onto itself and ct skin discard in trash; keep away from children and pets (Continued)

TABLE 32-2. AVAILABLE PRESCRIPTION TOPICEUTICALS (CONTINU Formulation Use Infor Prop LidoSite Topical Lidocaine 10% Relief of local pain One System (lidocaine and epinephrine caused by needle appl HCl/epinephrine 0.1% in a circular insertion into veins, profe topical iontophoretic reservoir, single- needle sticks for care patch 10%/0.1%) use patch; the blood draw, lasers minu and the LidoSite treatment side used to burn skin Controller and return lesions away in Appl reservoir on the upper skin intac B. Braun (Bethlehem, other side layers Pa.) complete the electrical circuit

ED) Common Side Effects Additional Tips for Use 248 CHAPTER 32 TOPICEUTICALS rmation for Electric current may For use in patients 5 per Use cause skin irritation, years old and older burning feeling, or Uses electric current to patch should be burns help the drug cross the skin; lied by a health care Skin under the patch not for use in someone with essional in a health may show short-lived electrically sensitive devices e setting for 10 skin whitening or (e.g., pacemakers) utes redness, rash, or pain/ Contains a sulfite (sodium burning sensations metabisulfite) that can pose ly only to allergic reactions of varying ct skin degrees Not tested for use on mucous membranes (Continued)

TABLE 32-2. AVAILABLE PRESCRIPTION TOPICEUTICALS (CONTINUE Formulation Use Infor Prop EMLA Cream Lidocaine 2.5% For use on normal Apply (lidocaine 2.5% and procaine 2.5% intact skin for local of cr and procaine in a cream (may pain relief or on dress 2.5%) use with Tegaderm genital mucous the c skin dressing) membranes for AstraZeneca minor surgery Crea (Wilmington, Del.) involving the upper size skin layers area, and as a appli pretreatment for depe more extensive skin type numbing procedures and t patie Used in adults for child blood draw needle sticks, genital wart removal; in children for blood draw needle sticks; in newborns prior to circumcision

ED) Common Side Effects Additional Tips for Use rmation for Skin paleness, Dressings are recommended redness, burning, to keep the cream in place per Use alternations in and to protect clothing temperature sensation, y a thick layer edema, itching, and Avoid contact with the eye ream and use a rash in the area of Use care when applying sing to cover patch application cream over large areas or cream leaving it on the skin for longer than 2 hours am amount required, of application Acutely ill, debilitated, , and length of older, or severe liver ication time vary disease patients may be more sensitive to ending on the body-wide effects of of procedure lidocaine/procaine the age of the ent (e.g., adult, d, newborn) CHAPTER 32 TOPICEUTICALS 249

250 CHAPTER 32 TOPICEUTICALS by blocking nerve signals (pain and other sensation [touch]) to the brain. The cream is applied to intact skin under a dressing that covers the skin and helps the cream from coming off (and also protects children from accidental ingestion). The disc has a backing, a cellulose disc (where the medication is located), and an adhesive tape ring. It covers a relatively small area, and the medication portion is in contact with the skin in an even smaller area (10 cm2). EMLA cream has been reported to be not as effective for long-term (chronic) pain conditions, including nerve pain. FUTURE DEVELOPMENTS 8. What topicals now in development may become available in the United States over the next few years? For many decades, topical nonsteroidal anti-inflammatory drug (NSAID) products have been prescribed in Asian and European countries with good success. Patients may be most familiar with NSAIDs available in tablet form (i.e., ibuprofen) that are swallowed. Anti-inflammatory medications relieve pain by treating the inflammation (i.e., swelling) that often makes pain feel worse. Formulations of several topical NSAIDs are being developed for the U.S. market. In addition, novel formulations of local anesthetics are being developed for the treatment of neuroma (abnormal regrowth of severed nerves) pain and headache disorders. New formulations of NMDA-antagonists, another class of medications, may help treat some neuropathic pain disorders also. KEY POINTS 1. Unlike transdermal agents, which require a systemic concentration to be effective, topical analgesics exert their effect via a local and not systemic mechanism. 2. Advantages of topical analgesics include a limited risk for drug-drug interactions, a limited risk for systemic side effects, and an analgesic treatment option for patients who cannot swallow pills and/or are fearful of needles. 3. Disadvantages of topical analgesics include accidental eye exposure and subsequent irritation, restriction of activities while using the topical agent (e.g., showering or swimming), and various skin reactions. 4. Future development of topical pain relievers in the United States may include the development of topical nonsteroidal antiinflammatory agents (NSAIDs) as well as NMDA receptor antagonists. BIBLIOGRAPHY 1. Argoff CE: Topical agents for the treatment of chronic pain, Curr Pain Headache Rep 10(1):11-19, 2006. 2. Galer BS, Gammaitoni A: Use of topiceuticals (topically applied, peripherally acting drugs) in the treatment of chronic pain, Current Drug Therapy 1:273-282, 2006. 3. Galer BS, Gammaitoni A, Alvaraz N: Pain, Scientific American Medicine, Chapter 10, Section XIV, 2001, WebMD.

NONSTEROIDAL ANTIINFLAMMATORY CHAPTER 33 DRUGS AND ACETAMINOPHEN Robert A. Duarte, MD, and Charles E. Argoff, MD 1. List the indications for treatment with aspirin, acetaminophen, and nonsteroidal antiinflammatory drugs (NSAIDs)? Aspirin, acetaminophen, and other NSAIDs are generally considered to be the drugs of choice for mild to moderate pain. They represent the first step in the analgesic ladder proposed by the World Health Organization. These agents have a relatively low abuse potential and are primarily used in nociceptive somatic pain syndromes, e.g., arthritis. They do, however, have a ceiling effect. Pure opioid analgesics such as hydromorphone and morphine do not. The ceiling effect refers to the dose after which additional quantities of an analgesic no longer provide additional analgesia. For example, 2000 mg of aspirin does not provide more analgesia than 1000 mg of aspirin and may lead to more side effects. 2. Describe the mechanism of action of the NSAIDs. The antiinflammatory effect of nonsteroidal antiinflammatory agents is due mainly to inhibition of the enzyme cyclooxygenase (COX), which is required for synthesis of prostaglandins and thromboxanes. There are two COX isoforms: COX1, which is expressed constitutively in most tissues and is thought to protect the gastric mucosa and platelets, and COX2, which is expressed constitutively in the brain and kidney but can be induced at sites of inflammation. Traditional NSAIDs are nonselective COX1 and COX2 inhibitors, whereas celecoxib is a selective COX2 inhibitor. 3. What are the major pharmacokinetic differences among the NSAIDs? All the NSAIDs possess similar absorption characteristics. In general, they are rapidly absorbed after oral and rectal administration. They are highly protein-bound and metabolized primarily in the liver. However, durations of action vary markedly. Some drugs, such as ibuprofen, require dosing every 4 to 6 hours, whereas piroxicam can be given once a day. The newer COX2 inhibitors also require only once or twice daily dosing. 4. List the most common side effects associated with the traditional NSAIDs. Gastrointestinal (GI) irritation, nausea, and impairment of platelet aggregation are the most common side effects associated with the traditional NSAIDs. These side effects may lead to dyspepsia, GI ulcers, and bleeding. Some of the nonacetylated salicylates (e.g., choline magnesium trisalicylate) do not inhibit platelet function. Other known side effects include peripheral edema and elevated blood pressure. 5. Describe the clinical presentation for acute acetaminophen overdose. Symptoms of acetaminophen overdose include vague abdominal pain during the first week, followed by signs of hepatic failure. At doses of 200 to 250 mg/kg, acetaminophen is hepatotoxic. Acetaminophen, at doses of 400 mg/kg, can be fatal. 6. What are the risks of combining NSAIDs with acetaminophen? The risk of analgesic nephropathy appears to increase when different NSAIDs are used together or in combination with acetaminophen. This effect is generally seen in long-term use. The primary lesion is papillary necrosis with secondary interstitial nephritis. 251

252 CHAPTER 33 NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND ACETAMINOPHEN 7. What is the risk of nephrotoxicty with NSAIDs? Aspirin and NSAIDs at therapeutic doses generally do not cause renal disease in patients with normal renal function. However, problems such as nephrotic syndrome, acute interstitial nephritis, and acute renal failure have been observed when aspirin and other nonsteroidals are given to patients with abnormal renal function. This can occur as a result of the inhibition of renal prostaglandin production by NSAIDs and the coxibs. Congestive heart failure, hepatic cirrhosis, collagen vascular disease, intravascular volume depletion, and arthrosclerotic heart disease are known contributing factors that may increase the risk of renal failure. 8. Which groups of NSAIDs are available in the United States? & Traditional, or nonselective, COX1 and COX2 Inhibitors ○ Salicylate (salsalate, diflunisal, and choline magnesium trisalicylate) ○ Proprionic (ibuprofen, ketoprofen, naproxen, fenoprofen) ○ Indole (indomethacin, sulindac, tolmetin) ○ Fenamate (mefenamic, meclofenamate) ○ Mixed (piroxicam, ketorolac, diclofenac) & Selective COX2 Inhibitors ○ Celecoxib (Celebrex) 9. Which agent is considered to be the drug of choice for pain control? There is no conclusive evidence supporting one NSAID over another for analgesia. Frequency of dosing, cost, and side-effect profile should be considered when deciding on a specific NSAID agent for pain control. Following a review of the overall efficacy of the NSAIDs and their potential risk for cardiovascular disease, the Food and Drug Administration (FDA) Arthritis Panel currently suggests Naprosyn, or Celebrex if there are risk factors that mitigate against the use of Naprosyn, as the preferred agents for the treatment of arthritis pain. 10. Describe an adequate trial of NSAIDs for pain control. An analgesic should not be considered a failure unless it has been given an adequate trial. For non–cancer-related pain, 2 weeks of treatment with a maximum scheduled dose constitutes an adequate trial. For cancer-associated pain, 1-week duration of continuous dosing is considered sufficient. However, ketorolac is not recommended for more than 5 days’ duration because of the risk of serious gastrointestinal and other side effects. 11. If one NSAID fails to provide sufficient pain relief, how should a clinician proceed? If an adequate trial of one class of NSAID does not cause analgesia, the clinician should switch to an alternative class of NSAID. For example, if an agent from a salicylate group is considered ineffective it is recommended to change to a proprionic or indole group. On the other hand, when one group of NSAID is effective but produces intolerable side effects, the clinician should first search for another agent in the same class before switching to another group of NSAID. 12. List the potential risk factors for the traditional NSAID-associated GI toxicity. & Advancing age & Concomitant administration of corticosteroids & History of either ulcer disease or prior GI complications from NSAIDs 13. What is the role of protective therapies in association with administration of traditional NSAIDs? To date, only misoprostol has been proved to reduce the risk for serious GI toxicity. Misoprostol diminishes the incidence of endoscopically detectable lesions. However, no evidence has confirmed that misoprostol diminishes the risk of complications from the lesions when they occur. Protective agents may be indicated in patients over the age of 60 years of age and patients with predisposition to GI problems.

CHAPTER 33 NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND ACETAMINOPHEN 253 14. Do the selective COX2 inhibitors have a lower risk for gastrointestinal toxicity compared to the traditional NSAIDs? Yes. The COX2 inhibitors were associated with a lower incidence of symptomatic ulcers compared with traditional NSAIDs at standard doses. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. 15. What are the major distinctions among the mechanisms of action of aspirin, acetaminophen, NSAIDs, and the COX2 inhibitors (coxibs)? Aspirin is an irreversible inhibitor of the COX enzymes. The exact mechanism of action of acetaminophen is not known. However, it is a weak nonselective inhibitor of both the COX1 and the COX2 enzymes. NSAIDs inhibit the activity of both COX1 and COX2 enzymes. The coxibs selectively inhibit the COX2 enzyme. 16. Which COX2 inhibitor(s) are currently available in the United States? Originally, there were three selective COX2 inhibitors in the United States. Presently, celecoxib is the only oral selective coxib available in the United States approved for osteoarthritis and rheumatoid arthritis. The FDA removed rofecoxib from the U.S. market because of increasing evidence that it increased risk for cardiovascular disease. Of note, valdecoxib was removed by the FDA primarily because of the high risk of skin lesions (i.e., Stevens-Johnson syndrome) attributed to it. 17. What are the documented precautions with celecoxib? Celecoxib is contraindicated in patients who have had an allergic-type reaction to sulfonamide drugs. This agent is not recommended for patients with severe hepatic insufficiency or advanced renal disease. In postmarketing studies, patients receiving celecoxib concurrently with warfarin experienced bleeding events in association with an increase in prothrombin time. Therefore, if celecoxib therapy is initiated or changed, the International Normalized Ration (INR) should be monitored, especially in the first few days. In addition, the clinician should be aware of the potential interaction with lithium and cytochrome P450 inhibitors when patients are taking celecoxib. 18. Discuss some cardiovascular issues associated with selective COX2 inhibitors. NSAIDs and coxibs do not provide the same protective effects as low-dose aspirin. Coxibs (selective COX2 inhibitors) decrease vascular prostacyclin (PGI2) production and may affect the balance between prothrombotic and antithrombotic eicosanoids. However, the available studies can suggest only that there is a potential increase in cardiovascular events compared to the traditional NSAIDs. In patients taking a coxib agent, the recommendation is to maintain low-dose daily aspirin in patients who are at significant risk of a cardiovascular event. However, the use of low-dose acetyl salicylic acid (ASA) does not consistently negate the potential cardiovascular risk of COX2 inhibitors. 19. List the potential central nervous system side effects associated with NSAIDs. All NSAIDs have the potential to produce central nervous system side effects, including sedation, dizziness, and headaches. Headaches occur in about 10% of patients taking indomethacin. Usually side effects are mild and transient. 20. What are the only parenteral NSAIDs available in the United States? Ketorolac and diclofenac is the only parenteral NSAID available in the United States. Doses of 10 to 30 mg parenteral ketoralac are equivalent to 10 to 12 mg of parenteral morphine. However, the risks of bleeding limit its use to no more than 5 days. Contraindications to ketorolac and diclofenac include a history or current risk of gastrointestinal bleeding, risk of renal failure, compromised homeostasis, hypersensitivity to aspirin or other NSAIDs, labor, delivery, and nursing. There are ongoing trials of parenteral forms of COX-2 inhibitors.

254 CHAPTER 33 NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND ACETAMINOPHEN KEY POINTS 1. Multiple nonsteroidal antiinflammatory medications (NSAIDs), including both nonselective agents and one selective agent, are commercially available. Unlike opioid analgesics, these medications appear to have a ceiling effect. 2. The risk for nephrotoxic effects appear to be increased when different NSAIDs are used in combination with each other or with acetaminophen. 3. If an adequate trial of one type of NSAID does not result in adequate pain relief, the clinician should consider switching the patient to a different type of NSAID. 4. The clinician should prescribe these drugs cautiously, especially in view of the potential for cardiovascular, gastrointestinal, and renal adverse effects. BIBLIOGRAPHY 1. Bombardier C, Laine L, Reicin A, et al: (The VIGOR Study Group): Comparison of upper gastrointestinal toxicity of rofecoxib and naproxyn in patients with rheumatoid arthritis, N Engl J Med 343:1520-1528, 2000. 2. Crofford LJ: Rational use of analgesic and anti-inflammatory drugs, N Engl J Med 345(25):1844-1846, 2001. 3. Giovanni G, Giovanni P: Do NSAIDs and COX 2 inhibitors have different renal effects? J Nephrol 15(5):480-488, 2002. 4. Macario A, Lipman AG: Ketorolac in the era of cyclo-oxygenase 2 selective nonsteroidal anti-inflammatory drugs: a systemic review of efficacy, side effects, and regulatory issues, Pain Medicine 2(4):336-351, 2001. 5. Mukherjee D, Nissan SE, Topol EJ: Risk of cardiovascular events associated with selective COX 2 inhibitors, JAMA 286:954-959, 2001. 6. Nikles CJ, Yelland M, Del Mar C, et al: The role of paracetamol in chronic pain: an evidence-based approach, Am J Ther, 12(1):80-91, 2005. 7. Olsen NJ: Tailoring arthritis therapy In the wake of the NSAID crisis, N Eng J Med 352:2578-2580, 2005. 8. Scheiman JM, Fendick AM: Practical approaches to minimizing gastrointestinal and cardiovascular safety concerns with COX 2 inhibitors, Arthritis Res Ther (Suppl 4):523-529, 2005. 9. Silverstein, FE, Faich G, Goldstein GL: Gastrointestinal toxicity with celecoxib vs. nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis, The Class Study, JAMA 284(10):1247-1255, 2000.

OPIOID ANALGESICS CHAPTER 34 Ronald Kanner, MD 1. Tolerance to the analgesic effects of opioids is well known. Does tolerance occur to the side effects, as well as the effects? Yes, tolerance occurs to the side effects, as well as the effects, but the rate of tolerance may be different. For example, pupillary constriction and constipation are chronic side effects that may continue as long as opioid dosing continues. However, tolerance to respiratory depression develops more rapidly. As opioid doses are increased to overcome analgesic tolerance, constipation and pupillary constriction persist, whereas respiratory depression may become less of a problem. 2. What is an opioid? ‘‘Opioid’’ is the term used to refer to a group of substances that have the analgesic and other properties of morphine. This includes the naturally occurring opiates, semisynthetic opiates, and endogenous opioids. The term ‘‘opiate’’ was initially used to denote any derivative of the poppy plant. As synthetic and semisynthetic products became available and endogenous peptides with morphinelike activity were identified, it became clear that the term had to be modified. It still holds some of its literary significance as any substance capable of assuaging suffering. 3. What is the role of opioids in pain management? Opioids have been the mainstay of treatment of moderate to severe pain in patients with cancer and in many acute pain syndromes. Although many patients with chronic noncancer pain have been successfully treated with opioids, their role in chronic pain of noncancer origin is still being defined. In the 1960s and 1970s, opioid treatment was considered the antithesis of good treatment for chronic pain of noncancer origin. In the 1980s and 1990s, it gained greater acceptance. For treatment of both cancer and noncancer chronic pain, there are few true long-term studies to help practitioners fully understand the potential benefits and risks of such therapy. In recent years, guidelines have been established for the safe and efficacious use of opioids in the treatment of many noncancer pain syndromes. The guidelines suggest that opioid therapy for chronic noncancer pain should be considered only after other reasonable attempts at analgesia have failed. A history of substance abuse or severe character pathology should be considered relative contraindications. One practitioner should manage the prescribed opiates, and he or she must be experienced in their use and able to recognize and deal with adverse reactions such as cognitive impairment, constipation, and aberrant use. The potential risks and benefits should be discussed with the patient and clearly documented in the patient file. New guidelines regarding the use of opioids in chronic noncancer pain are being developed as a collaborative effort among several major pain organizations and should be available soon. 4. What is a narcotic? Narcotic is now a term that has more legal implications than it does pharmacologic ones. It was initially used to denote any drug capable of producing sleep (narcosis). It was generally applied to the opiates. However, the term is now used to denote drugs of abuse that are controlled by government agencies. The old name for one of the federal agencies was the Bureau of Narcotics 255

256 CHAPTER 34 OPIOID ANALGESICS and Dangerous Drugs. Currently, the main regulatory agency on a national level is the Drug Enforcement Agency (DEA). The term opioid is now preferred instead of narcotic when describing opioid analgesics. 5. What are the two main, naturally occurring opioid alkaloids used in clinical practice? Morphine and codeine are two of the most widely used naturally occurring opioid alkaloids. Morphine is the prototype of the opioid drug. It binds primarily to mu receptors, producing analgesia and respiratory depression. 6. Describe the mechanism of opioid analgesia. Opioid analgesia is thought to be mediated through a direct interaction with an opioid receptor. Thus far, the opioid receptors responsible for analgesia have been identified in the spinal cord, the brainstem, and the cerebral cortex. It is less clear at present what analgesic role is played by the opiate receptors that have been identified in the peripheral nervous system. 7. What is the difference between a ‘‘weak’’ and a ‘‘potent’’ analgesic? The weak analgesics have a ceiling effect. This implies that there is a dosing level after which side effects accrue more rapidly than analgesic effects. The potent opioids have no such ceiling. As tolerance develops or disease progresses, the doses can be increased. 8. Name some of the ‘‘weak’’ opioids and the problems associated with them. Codeine is one of the most commonly used weak opioids. As doses escalate, nausea and constipation limit efficacy. For example, though 30 mg of codeine provides more analgesia than 15 mg, and 60 mg provides more than 30 mg, etc., higher doses are limited by side effects. Oxycodone is often listed as a weak opioid. However, this designation is mainly a function of the acetaminophen or aspirin with which it is commonly combined, and in reality, oxycodone by itself is likely more potent than morphine. When used as a single agent and not in combination with another agent, oxycodone can be given in increasing doses, without as clear a ceiling. 9. Name some ‘‘potent’’ opioids. Morphine is the prototype of the potent group, against which other opioids have been judged despite the fact that other commonly prescribed drugs, including hydrocodone and oxycodone, are more potent than morphine. Morphine is a relatively short serum half-life drug (2 to 3 hours), as is hydromorphone. Methadone, another potent opioid, has a much longer terminal serum half-life, potentially extending to 54 hours; however, its analgesic serum half-life is often much shorter (6 to 8 hours, for example). Prescribing methadone in particular can be very challenging as a result because increasing the dose too quickly can lead to serious and potentially fatal outcomes. 10. What subtypes of opioid receptor are important in analgesia? The three main opioid subtypes are the mu, kappa, and delta receptors. From the standpoint of analgesia, the mu receptor seems to be the most important. There may be subtypes of these receptors, with different drugs having different affinities for given receptor subtypes and different patients having different receptor subtypes as well. There also may be analgesic activity at the delta and kappa sites. 11. Explain what is meant by a mixed agonist-antagonist drug. When a drug combines with a receptor site and produces the action of that receptor, it is considered an agonist. A drug that binds with a receptor and inhibits activity is considered an antagonist. Naloxone is an example of a pure antagonist drug. Semisynthetic and synthetic products have been produced that are both agonist and antagonist at opioid receptors. The hope in producing these drugs was that they would be agonist for analgesic effects and antagonist for the respiratory depression and sedative effects of the opioids. Examples of mixed agonist- antagonist drugs include pentazocine, butorphanol, and buprenorphine. New preparations of these drugs, specifically buprenorphine, are being or have been developed. In fact, the

CHAPTER 34 OPIOID ANALGESICS 257 administration of a mixed agonist-antagonist drug to a patient who is physically dependent on an agonist may produce a withdrawal syndrome. 12. What are the endogenous opioids? The first endogenous opioids to be discovered were the endorphins and enkephalins. These are polypeptides that are synthesized in the brain and spinal cord. They bind with opioid receptors and produce analgesia. Since the discovery of endorphins and enkephalins in the early 1970s, a number of other peptide products have been described. 13. How do mixed agonist-antagonist drugs differ from pure agonist analgesics? Clinically, the most important concept is that these mixed drugs have a ceiling effect. That is, with increasing doses, side effects supervene, and further analgesia cannot be achieved. When tolerance develops to pure agonist drugs, drug doses can be increased to obtain further analgesia. In patients who are opioid dependent, administration of a mixed agonist-antagonist may precipitate withdrawal. 14. Differentiate efficacy and potency. Efficacy refers to the ability of the drug to produce a given response in an appropriate clinical setting. Potency refers either to the number of milligrams required to produce an effect or to the affinity with which a drug binds to a receptor. Thus a drug may be very potent (able to produce a response at a very low dose) but not have great efficacy (because of intolerable side effects). 15. If a patient is taking a potent opioid, how can it make sense to add a nonsteroidal antiinflammatory drug to the regimen? Opioids and nonsteroidal antiinflammatory drugs work at different sites. As noted earlier, the opioids combine with the opioid receptor, primarily in the central nervous system. The nonsteroidal antiinflammatory drugs are cyclooxygenase inhibitors and their primary site of action is in the peripheral nervous system. 16. What is meant by an equianalgesic dose? Most studies done to determine the clinical potency of the opioid analgesics were done against a standard dose of 10 mg of intramuscular (IM) morphine. Thus the number of milligrams of a given drug required to produce the same degree of analgesia as 10 mg of morphine is referred to as the ‘‘equianalgesic dose.’’ Most opioids are far more potent when given parenterally than orally. To achieve a dose equianalgesic to 10 mg of IM morphine, 20 to 60 mg would have to be administered orally. This is because of a ‘‘first pass’’ effect in the liver: approximately 50% to 80% of an opioid is inactivated by hepatic metabolism after oral administration. The extent of this first pass effect varies from drug to drug. Hydromorphone, for example, is five times as potent on a milligram basis after IM injection than it is after oral administration. Methadone, on the other hand, has only a 2:1 ratio. 17. By the intramuscular route, what are the equianalgesic doses of hydromorphone, methadone, demerol, and levorphanol that would equate with 10 mg of intramuscular morphine? To match the analgesic effects of a 10-mg dose of IM morphine, a patient would require 1.5 mg of hydromorphone, 10 mg of methadone, and 2 mg of levorphanol. (See Table 30-5 for equianalgesic doses of various opioids; this information is also available in most pharmacology textbooks.) 18. Do these calculations hold for chronic dosing? No, the equianalgesic calculations do not necessarily hold for chronic dosing. Unfortunately, there is a paucity of data on long-term dosing, and there appears to be a very wide range of ratios that do not fit the numbers cited in Question 16, which were derived from acute dosing. Importantly, methadone appears to be much more potent than previously estimated. When switching to methadone from another opioid, the calculated dose should be decreased by about 75%! Discrepancies may also exist depending on the direction of the switch (methadone to morphine, or morphine to methadone).

258 CHAPTER 34 OPIOID ANALGESICS 19. What are the major differences among the opioid analgesics? The first major difference is between agonists and mixed agonist-antagonist drugs. The relatively pure opioid agonists include drugs such as morphine, codeine, oxycodone, oxymorphone, levorphanol, fentanyl, and methadone. The mixed agonist-antagonist drugs that are in popular use are pentazocine, butorphanol, and buprenorphine. The next major differentiation is between long serum half-life and short serum half-life. Methadone and levorphanol are two of the most commonly used long serum half-life drugs, having a half-life of anywhere from 12 to over 50 hours. (With prolonged use, half-life extends markedly.) Morphine and hydromorphone are prototypes of the short serum half-life drugs. 20. What are appropriate dosing intervals for the opioid analgesics? When used as immediate-release products, morphine and hydromorphone should generally be dosed every 2 to 4 hours. If a sustained-release or controlled-release product is used, morphine can be dosed every 8 to 12 hours. The long serum half-life drugs may have a greater duration of efficacy and can often be dosed every 4 to 6 hours. Despite the long serum half-life, analgesic efficacy does not directly parallel the serum half-life. 21. What is a rescue dose? Patients who are treated with a sustained-release product may have breakthrough pain (unexpected increases in pain that was previously well controlled) and require intermittent doses of an immediate-release product. It is probably best to use the same medication for the rescue as for the standing dose. It should be offered on an as needed basis every 2 to 3 hours and should be approximately 10% of the total daily dose. 22. What routes of administration are available for the opioids? Opioids can be successfully delivered by virtually any route. In general, the most convenient route is orally. However, allowances must be made for the ‘‘first pass’’ effect in the liver (see Question 16). When given by the parenteral route, opioids are anywhere from two to five times as potent on a milligram basis than when given orally. They are also readily absorbed after subcutaneous injection and can be administered intravenously. Rectal and sublingual preparations are also available for some opioids. Fentanyl is available as a transdermal patch. In general, the intramuscular route should be avoided. The injection itself is painful and offers little or no advantage over the subcutaneously or intravenous routes. 23. What are the benefits and drawbacks of transdermal fentanyl? Fentanyl is a relatively potent opioid analgesic. The application of a transcutaneous patch allows for relatively stable serum levels of fentanyl over 48 to 72 hours. This cuts down the need for repeated dosing and for the pain of parenteral administration. However, after application of the first patch, there is a delay of 12 to 24 hours in achieving adequate analgesia. During this time, rescue doses must be given. Furthermore, if side effects ensue, removal of the patch will not immediately eliminate them because a subcutaneous reservoir of drug has been formed. The dose of drug is directly related to the surface area of the patch. It is available as 12, 25, 50, 75, and 100 micrograms per hour. Direct equianalgesic studies with morphine have not been published, but a 100-micrograms-per-hour patch applied every 72 hours is approximately equianalgesic to 200 mg per day of morphine. 24. What are some of the adverse reactions that are peculiar to the transdermal application of opioids? Absorption varies with the state of vascular dilatation. Fever or local heat can produce vasodilatation that produces more rapid absorption and systemic distribution of the opioid preparation. Patients must be cautioned not to apply a heating pad to the area where the patch is applied. Local reactions to the adhesive have also been described.

CHAPTER 34 OPIOID ANALGESICS 259 25. List some of the most common side effects of the opioids. Constipation is the most common and bothersome clinical side effect of the opioids. It is usually defined as a reduction in the frequency of bowel movements to less than one every three days, or difficulty in passing stool. Although respiratory depression, tolerance, dependence, and addiction get the lion’s share of the adverse press, constipation is the problem the clinician most often has to address. It is also a complication to which tolerance does not usually develop. All patients being started on opioid analgesics should be given a bowel regimen. In general, a combination of the senna alkaloids and a stool softener is sufficient. However, care should be taken not to allow constipation to progress too far. Once the patient has missed more than a few days of bowel movements, disimpaction may be necessary. Nausea and vomiting are not uncommon at the start of opioid therapy. However, tolerance usually occurs within days to weeks, and a specific therapy is not usually required. If nausea persists, opioid rotation may be tried, or the route of administration may be changed. Neuroendocrine side effects including hypogonadism need to be considered in patients on chronic opioid therapy. 26. Under what circumstances is respiratory depression a serious worry in patients treated with opioids? If opioids are used carefully, in gradually increasing doses, respiratory depression usually is not a problem. However, there are two circumstances in which respiratory depression may occur unexpectedly. First, when using long serum half-life drugs, remember that five serum half-lives are required to reach steady state. Thus, when using a drug such as methadone or levorphanol, it may require more than a week to achieve steady state. During this titration period, great care must be taken because serum levels may be escalating despite stable dosing. The second circumstance occurs in patients who undergo a pain-relieving procedure after they have been on large doses of opioids. Patients may tolerate large doses while they are in pain. However, if they undergo radiation therapy, cordotomy, or some other procedure directed at the pain syndrome itself, they may no longer be as tolerant to the opioids. Patients should be monitored carefully for a number of days following these procedures. If respiratory rate decreases or they become overly somnolent, doses should be cut back. On the rare occasion that an opioid antagonist must be administered for severe respiratory depression, it should be diluted and injected slowly to avoid the risk of a severe withdrawal syndrome. 27. How should opioid overdose be treated? Treatment depends directly on the situation in which the overdose has occurred and the severity of side effects. If there is only somnolence, without respiratory depression, simply cutting back on the dose or holding a few doses is usually enough to reverse the side effects. If there is severe respiratory depression, more urgent measures are required. In these cases, naloxone may be administered intravenously. However, if it is given as a bolus, patients who have been taking opioids chronically may experience withdrawal. Therefore, naloxone should be diluted in 10 ml of saline and administered slowly. Keep in mind that opioids primarily depress respiratory rate. Therefore, simply counting respirations as they increase is enough to judge efficacy of opioid reversal. Naloxone, however, has a much shorter serum half-life than most opioids. Repeated doses may be required. 28. What is meant by tolerance? What are its clinical manifestations? Tolerance refers to a situation in which decreased effects are noticed despite stable doses of a drug, or increasing doses of a drug are required to maintain a given effect. In experimental models, this can develop quite rapidly. Clinically, however, many patients with stable pain syndromes can be maintained on steady doses of opioids for prolonged periods of time. As pain increases (as with advancing cancer), progressively higher doses of drug may be used to control pain. In these cases, increasing analgesia may occur without significant respiratory depression or somnolence.

260 CHAPTER 34 OPIOID ANALGESICS 29. Define physical dependence. Physical dependence is a state in which rapid discontinuation of a drug or administration of an antagonist produces an abstinence syndrome. With the opioids, an abstinence syndrome is characterized by abdominal discomfort, borborygmus, goose flesh, nausea, and yawning. In addicted subjects, there is marked drug craving. In nonaddicted subjects, there is simply severe discomfort. 30. Does physical dependence define addiction? No. Physical dependence can develop entirely separate from addiction. Although ‘‘psychological dependence’’ has often been used interchangeably with addiction, physical dependence (as defined earlier) is a physiological phenomenon that occurs as a result of repeated administration of a drug. The mechanism of physical dependence occurs at a molecular level, not a societal one. 31. What is meant by opioid addiction? Addiction is a biopsychosocial condition in which there is psychological dependence on a drug, preoccupation with securing its supply, use despite harm, use for nonmedical purposes, and a high incidence of recidivism. This is actually quite rare in patients treated appropriately with opioids for pain. Even in patients with pain of nonmalignant origin, opioid addiction is quite uncommon. (See Chapter 35, Addiction and Pain Management, for a more thorough discussion of the subject.) 32. What is opioid unresponsiveness? How can it be handled? Opioid responsiveness is the analgesia that can be achieved from opioids as the dose is titrated to an endpoint defined either by intolerable side effects or the occurrence of acceptable analgesia. By contrast, if side effects impose a limit on dose escalation, the pain is said to be relatively opioid unresponsive. There is always a balance between effects and side effects. A number of factors can influence opioid responsiveness, including the type of pain (neuropathic pain is often relatively unresponsive), the temporal pattern of the pain (incidence of pain may be difficult to control), opioid tolerance or disease progression (may require very high doses), and idiosyncratic patient issues (may limit responsiveness). Strategies to overcome opioid unresponsiveness include more aggressive management of side effects (an attempt to ‘‘open the therapeutic window’’), the use of adjuvant drugs that may have analgesic effects of their own, the use of drugs that may enhance opioid analgesia (calcium-channel blockers and clonidine), or ‘‘opioid rotation.’’ 33. Describe ‘‘opioid rotation.’’ What is the rationale behind it? Cross-tolerance among the opioids is not complete; a patient who is tolerant to a given opioid may not be completely tolerant to a different opioid. If analgesia cannot be obtained with a specific drug, it may make sense to try different opioids. This can be done sequentially, until an appropriate balance is found between analgesia and side effects. 34. What is patient-controlled analgesia? As generally used today, patient-controlled analgesia (PCA) refers to an arrangement whereby patients are able to administer their own drugs on a set basis. Usually this is by the intravenous route. Intravenous access is established, and a system is attached by which the patient may bolus small amounts of opioid every few minutes. A ‘‘lockout period’’ is also established to avoid overdosing. PCA can be done with or without a continuous infusion. This modality is most often used for patients in acute pain settings, such as those experiencing postoperative pain.

CHAPTER 34 OPIOID ANALGESICS 261 KEY POINTS 1. Opioid analgesics may be effective for both cancer and noncancer pain. 2. There are many different opioid analgesics currently available; the prescriber should be knowledgeable of the relative potency of the prescribed drugs and other unique characteristics of specific drugs before prescribing them. 3. Opioid analgesics are available as short acting and longer acting preparations. 4. Opioid analgesics may be administered through multiple routes depending on patient needs and, in some instances, patient preference. 5. The prescriber needs to be aware of the risks of opioids, including aberrant behaviors, as well as potential adverse effects and must screen for these and monitor for these before and during treatment with opioids. BIBLIOGRAPHY 1. Anderson R, Saiers JH, Abram S, Schlicht C: Accuracy in equally analgesic dosing: conversion dilemmas, J Pain Symptom Manage 21(5):397-406, 2001. 2. Angst MS, Clark JD: Opioid-induced hyperalgesia: a qualitative systematic review, Anesthesiology 104(3): 570-587, 2006. 3. Arnold RM, Han PK, Seltzer D: Opioid contracts in chronic nonmalignant pain management: objectives and uncertainties, Am J Med 119(4):292-296, 2006. 4. Aronoff GM: Opioids in the chronic pain management: is there is significant risk of addiction? Curr Rev Pain 10(2):112-121, 2000. 5. Dean M: Opioids in renal failure and dialysis patients, J Pain Symptom Manage, 28(5):497-504, 2004. 6. Mehta V, Langford RM: Acute pain management for opioid dependent patients, Anaesthesia 61(3):269-276, 2006. 7. Mercandante S, Portenoy RK: Opioid poorly-unresponsive cancer pain. Part 1: Clinical considerations, J Pain Symptom Manage 21(2):144-150, 2001. 8. Murray A, Hagen NA: Hydromorphone, J Pain Symptom Manage 29(Suppl 5):57-66, 2005. 9. O’Mahony S, Coyle N, Payne R: Current management of opioid-related side effects, Oncology 15(1):61-82, 2001. 10. Page GG: Immunologic effects of opioids in the presence or absence of pain, J Pain Symptom Manage 29(Suppl 5):25-31, 2005. 11. Paice JA, Toy C, Shott S: Barriers to cancer pain relief: fear of tolerance and addiction, J Pain Symptom Manage 16(1):1-9, 1998. 12. Passik SD, Weinreb HJ: Managing chronic nonmalignant pain: overcoming obstacles to the use of opioids, Adv Ther 17(2):70-83, 2000. 13. Pasternak GW: Molecular biology of opioid analgesia, J Pain Symptom Manage 29(Suppl 5):2-9, 2005. 14. Pereira J, Lawlor P, Vigano A, et al: Equianalgesic dose ratios for opioids: a critical review and proposals for long-term dosing, J Pain Symptom Manage 22(2):672-687, 2001. 15. Portenoy RK: Opioid analgesics. In Portenoy RK, Kanner RM, editors: Pain management: theory and practice, Philadelphia, 1996, FA Davis, pp 248-276. 16. Portenoy RK: Opioid therapy for chronic nonmalignant pain: a review of critical issues, J Pain Symptom Manage 11(4):203-217, 1996. 17. Reissig JE, Rybarczyk AM: Pharmacologic treatment of opioid-induced sedation in chronic pain, Annals of Pharmacotherapy 39(4):727-731, 2005.

ADDICTION AND PAIN MANAGEMENTCHAPTER 35 Ronald Kanner, MD, FAAN, FACP 1. What is addiction? Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. This definition was accepted by the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine in February of 2001. It implies that addiction is neither tolerance nor physical dependence, but a more complex, biopsychosocial phenomenon. 2. Is addiction common in patients treated with opioid analgesics for chronic pain syndromes? Regarding addiction in patients treated with opioid analgesics for chronic pain syndromes, prevalence figures in various studies have ranged from 1% up to 45%. The low end of the range was based on a study that looked only at patients who had received a single-dose of an opioid during a hospital stay for a non–drug-use-related problem. It is, perhaps, not a figure with great applicability, because it is far lower than the likely true prevalence of opioid addiction in the general population. The higher number was derived from a study that examined a small group of patients with a history of prior opioid addiction now treated with opioids for chronic pain. Although it is a strikingly high number, it also shows that up to 55% of patients—even with a prior history of addiction—can be treated successfully with opioids. The real addiction risk lies somewhere in between these two figures and is determined by a number of factors. (See Chapter 34, Opioid Analgesics, for a discussion of the issues that must be taken into account when prescribing opioids for chronic pain of noncancer origin.) When opioids are used appropriately for pain management, the risk of de novo addiction is likely acceptably low. As the work done by the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine has suggested, ‘‘Addiction, unlike tolerance and physical dependence, is not a predictable drug effect, but represents an idiosyncratic and chronic adverse reaction in biologically and psychosocially vulnerable individuals. Addiction is a primary chronic disease, and exposure to drugs is only one of the etiologic factors in its development.’’ 3. List the five main characteristics of addiction. The five C’s can be used as a memory aid for recalling the five main characteristics of addiction: Chronic Control impaired Compulsive use Continued use, despite harm Craving 4. What is physical dependence? Physical dependence is a state of adaptation that is manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, 262

CHAPTER 35 ADDICTION AND PAIN MANAGEMENT 263 decreasing blood level of the drug, and/or administration of antagonist. The presence of physical dependence does not, in itself, define addiction. It should be kept in mind that physical dependence is not unique to opioids. 5. What is tolerance? Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. The presence of tolerance does not, in itself, define addiction. 6. A patient is using progressively higher doses of the opioids prescribed and is requiring prescriptions sooner than anticipated. What are some of the possible causes? & Worsening of the underlying disease. This is the most common cause of dose escalation in patients with pain caused by cancer. Whenever a cancer patient has a worsening pain syndrome, the underlying disease should be the primary suspect. & Tolerance. One of the first signs of tolerance in the patient being treated with opioid analgesics is a shortening of the duration of action. The patient may not need a higher dose, but he or she may require more frequent dosing. Care should be individualized. & Drug diversion. Persons other than those for whom the drug is prescribed may be taking them. This could be a family member or friend, without the knowledge of the patient, or the patient may be intentionally giving or selling the drugs to a third party. & Addiction. 7. What is the utility of written medication agreements in patients suspected of opioid abuse? Although a written agreement may provide some security to the prescriber, it can have mixed effects. It is unclear that it prevents abuse or that it would have any legal standing. In some patients, it may create an unneeded friction between the patient and physician. However, it can be used as a means for the prescriber to outline what he or she expects from the patient with respect to appropriate medication use. 8. What should be done if addiction is suspected? Addiction is an uncommon and undesirable side effect of chronic opioid treatment. Recognize it as such. Conduct a frank discussion with the patient regarding addiction. If necessary, referral to an addiction specialist can be beneficial. Although it is not illegal to prescribe opioid medications to an addicted patient for pain control, it is illegal to prescribe methadone for addiction maintenance therapy, outside of an approved addiction therapy center. 9. What are some of the newer options for the outpatient management of opioid dependence? Buprenorphine (a partial opioid agonist) and the combination product of buprenorphine/ naloxone have recently been approved for the outpatient treatment of opioid dependence. As a partial agonist, buprenorphine can suppress some of the withdrawal symptoms that dependent patients can feel upon a limitation of their drug. It is less likely to produce significant respiratory depression. These treatments should be used only by physicians with adequate training and sufficient support staff to supply the needed medical and psychological support for these patients. 10. Even though methadone is a good analgesic, do patients on methadone maintenance therapy still require postoperative medications? Yes. Although methadone has a very long serum half-life (17 to 54 hours) and can effectively block symptoms of withdrawal during that time, its analgesic efficacy is only about 4 to 8 hours. If methadone is to be used as analgesic, it would have to be dosed at least three times per day.

264 CHAPTER 35 ADDICTION AND PAIN MANAGEMENT 11. Can other analgesics be efficacious in patients who are on methadone maintenance therapy? Yes. During the postoperative period, a reasonable program is to cover the patient’s prior methadone intake and add short serum half-life analgesics for acute pain management. 12. Is there strong evidence to suggest that hydromorphone is more likely to be abused than other opioid analgesics? No. Hydromorphone is not more likely to be abused than other opioid analgesics. This is urban legend that has not been substantiated by any appropriately designed studies. 13. Define pseudoaddiction. Pseudoaddiction is a term used to describe patient behaviors that may occur when pain is undertreated. Patients may embellish their symptoms in an attempt to obtain enough medication to provide adequate pain relief or may merely express their discomfort and hoard their medications for times of severe pain. These behaviors are interpreted by the physician as signs of addiction, and medications are cut back further. This leads to a vicious cycle in which the patient is requesting more and more drug to relieve pain, and the physician is prescribing less and less, because of the fear of addiction. 14. What is DAWN? DAWN is the Drug Abuse Warning Network. It records drug-related mentions in emergency reports. Data suggest that prescription drugs account for about 25% to 30% of all drug abuse. This figure has remained stable over a number of years. 15. True or false: ‘‘Overprescribing’’ and ‘‘underprescribing’’ are helpful terms when considering a therapy regimen. False. Overprescribing and underprescribing are relatively useless terms. What is more important is ‘‘appropriate prescribing practices.’’ If drugs are used for legitimate medical purposes, in the usual course of professional practice, and documented in medical records, it is highly unlikely that any legal action could be successfully taken against the practitioner. 16. What types of action on the part of the practitioner typically lead to sanctions from regulating bodies? Activities involving sex for drugs, money for drugs, and drugs for drugs are the types of practitioner actions that typically lead to sanctions from regulating bodies. Some physicians have actually kept records of their illicit activities, noting what they expected to receive in turn for the prescriptions. 17. Is there any relationship between the ‘‘street value’’ of the drug and the likelihood of its deviation from legal, prescribed uses? Yes. The ‘‘street value’’ of a given drug depends on a number of issues. Rapidity of onset, intensity, short duration of action, potency, the ability to create an injectable form, and brand recognition all may lead to greater desirability of a drug and therefore also lead to a greater likelihood that it will be misused. 18. How common are severe penalties against physicians for violations of the Controlled Substances Act? In the year 2000, controlled substances violations represented 7% of the total actions against physicians. Only 9% of those resulted in license revocation. 19. What actions on the part of the patient should alert you to the possibility of ‘‘drug-seeking’’ behavior? Any of the following may be a red flag that drug diversion or illicit use is occurring: & Frequent calls when another practitioner is covering & Calls toward the end of office hours, when a patient cannot be seen in person

CHAPTER 35 ADDICTION AND PAIN MANAGEMENT 265 & Requests for drugs without requesting evaluation & Urgent need for drugs & Unwillingness to provide prior medical records & Frequent complaints of ‘‘lost prescriptions’’ & Lack of follow-up on referrals 20. How can a practitioner prevent drug diversion? The first rules to follow to help prevent drug diversion are the same rules of good medical practice: perform a detailed history and physical examination, and document your diagnosis and treatment plan. If you see any of the signs of drug-seeking behavior, discuss them with the patient, document it in the chart, and seek expert help, if needed. Be aware of state and federal laws and regulations. You may want to use prescription pads that are not easily copied and carry serial numbers. Prescription pads should be kept in a safe place and not made available to other practitioners. It is good practice to write numbers out fully. Designate the number of refills, even when it is ‘‘zero.’’ Consider using risk assessment tools such as the Opioid Risk Tool (ORT) before prescribing to help you understand if the patient you are about to prescribe opioids to is at low, medium, or high risk of misusing the prescription. You can then decide if a particular patient is at an acceptable risk level for YOUR practice. If the patient’s risk level is considered by you to be high, BUT you feel the patient is still an appropriate candidate for opioid treatment, consider referring the patient to a subspecialist for comanagement. Define to the patient when initially prescribing opioids what you feel is a minimally acceptable clinical response for continuing a patient on such therapy. Moniter the patient carefully while on opioid therapy for benefits and adverse effects of such treatment, and specifically consider random urine drug testing to help ensure that the patient is using the prescription appropriately. 21. What resources are available to learn more about signs, risks, and treatments for addiction? The American Society of Addiction Medicine maintains a website that can be quite helpful. The American Academy of Pain Medicine and the American Pain Society also offer a number of publications regarding addiction medicine. KEY POINTS 1. Addiction is a chronic neurobiologic disorder that needs to be distinguished from tolerance and physical dependence. 2. Even patients with known drug addiction may need to be treated with opioid analgesics and under most circumstances, with appropriate training of the prescriber and with appropriate monitoring of the patient, this is considered appropriate. 3. Prescribers should be aware of ‘‘best’’ practice approaches to the prescribing of opioids to patients in general, as well as to known addicts in particular, and implement these in their practice.

266 CHAPTER 35 ADDICTION AND PAIN MANAGEMENT WEBSITES 1. U.S. Drug Enforcement Administration http://www.usdoj.gov/dea/agency/mission.htm 2. http://www.projectphysicianquality.org/jcaho.htm 3. University of Wisconsin: Pain & Policy Studies Group http://www.medsch.wisc.edu/painpolicy 4. American Pain Society http://www.ampainsoc.org 5. American Academy of Pain Medicine http://www.painmed.org BIBLIOGRAPHY 1. Alford DP, Compton P, Samet JH: Acute pain management for patients receiving maintenance methadone or buprenorphine therapy, Annals of Internal Medicine 144(2):127-134, 2006. 2. American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine: Consensus Document: Definitions related to the use of opioids for the treatment of pain. April, 2001. 3. American Society of Addiction Medicine: Public policy statement on definitions related to the use of opioids in pain treatment, J Addict Dis 17(2):129-133, 1998. 4. Arnold RM, Han PK, Seltzer D: Opioid contracts in chronic nonmalignant pain management: objectives and uncertainties, Amer J Med 119(4):292-296, 2006. 5. Compton P, Darakjian J, Miotto K: Screening for addiction in patients with chronic pain and ‘‘problematic’’ substance use: evaluation of a pilot assessment tool, J Pain Symptom Manage 16(6):355-363, 1998. 6. Fiellin DA, Kleber H, Trumble-Hejduk JG, McLellan AT, Kosten TR: Consensus statement on office-based treatment of opioid dependence using buprenorphine, Journal of Substance Abuse Treatment 27(2):153-159, 2004. 7. Mehta V, Langford RM: Acute pain management for opioid dependent patients, Anaesthesia 61(3):269-276, 2006. 8. Murray A, Hagen NA: Hydromorphone, J Pain Symptom Manage 29(Suppl 5):57-66, 2005. 9. Passik SD, Kirsh KL, McDonald MV, et al: A pilot survey of aberrant drug-taking attitudes and behaviors in samples of cancer and AIDS patients, J Pain Symptom Manage 19(4):274-286, 2000. 10. Passik SD, Portenoy RK, Ricketts PL: Substance abuse issues in cancer patients. Part 1: Prevalence and diagnosis, Oncology (Wiliston Park) 12(4):517-521, 524, 1998. 11. Passik SD, Weinreb HJ: Managing chronic nonmalignant pain: overcoming obstacles to the use of opioids, Adv Ther 17(2):70-83, 2000. 12. Portenoy RK: Opioid therapy for chronic nonmalignant pain: a review of the critical issues, J Pain Symptom Manage 11(4):203-217, 1996. 13. Portenoy RK, Dole V, Joseph H, et al: Pain management and chemical dependency: evolving perspectives, JAMA 278(7):592-593, 1997. 14. Sung S, Conry JM: Role of buprenorphine in the management of heroin addiction, Annals of Pharmacotherapy, 40(3):501-505, 2006. 15. Weissman DE, Haddox JD: Opioid pseudoaddiction—an iatrogenic syndrome, Pain 36(3):363-366, 1989.

REGULATORY ISSUES CHAPTER 36 Ellen Cooper, MS 1. Do patients with painful medical conditions generally receive adequate treatment for pain? No. Both acute pain and chronic pain caused by cancer are generally undertreated. This is particularly true of treatment with opioid drugs. Surveys of patients in the postoperative period demonstrate that up to 75% suffer pain of moderate or severe intensity. Because virtually all postoperative pain can be controlled with proper medication, an alarmingly high number of patients suffer from unnecessary pain. Similarly, in patients with advanced cancer, simple drug regimens can provide relief for more than 70%. However, 70% of patients with advanced cancer still report significant pain! On a global scale, the statistics are even more alarming. More than 3.5 million people suffer from cancer pain, but only a small fraction receives adequate treatment. This is particularly striking in view of the fact that pain can be controlled with appropriate drug regimens in approximately 90% of these patients. 2. What factors stand in the way of adequate pain treatment? Barriers to good analgesic therapy exist on the professional, societal, and governmental levels. From a professional point of view, physicians and nurses often have the misconception that the prescription of opioid medications will lead inexorably to tolerance, dependence, and addiction. Even physicians who understand that this is not true tend to underprescribe medications, possibly because of fear of other side effects. Furthermore, worry about regulation by outside agencies also tends to impede a physician’s prescribing practices. Many physicians do not understand government regulations on opioid prescribing, and their concerns are often unjustified. Certain government regulations, however, do limit prescribing practices. For example, in states that require a triplicate prescription for opioid medications, opioid prescribing decreases by about 50%. Patients also have many misconceptions about opioids. Their fear that the opioids represent a ‘‘last-ditch effort’’ makes them reluctant to take these drugs early in their disease. They also may be afraid of addiction, other side effects, or the societal stigma that goes along with taking opioid medications. 3. Are patients with medical illness and no history of substance abuse at significant risk of addiction if opioids are administered? Studies in patients with cancer have demonstrated that the main reason for escalating drug intake is progression of disease rather than aberrant behavior. This same pattern has been demonstrated in patients with pain caused by noncancer conditions. Although tolerance and physical dependence may occur, addiction is a rather rare phenomenon in patients treated appropriately with opioid medications for their pain. (See Chapter 35, Addiction and Pain Management.) 4. What are the differences among opiates, opioids, and narcotics? ‘‘Opioid’’ is a generic term used to refer to codeine, morphine, and other natural and synthetic drugs whose effects are mediated by specific receptors in the central and peripheral nervous 267

268 CHAPTER 36 REGULATORY ISSUES systems. The original term, ‘‘opiate,’’ was taken to mean any derivative of Papaver somniferum, the poppy plant that produces opium. Opioid also includes the endogenous opioids, such as endorphins and enkephalins. The term ‘‘narcotic’’ was initially used to denote a drug capable of producing sleep (narcosis). It was mainly applied to the opioids. However, narcotic is now more of a legal term, used in reference to all substances covered by the 1961 Single Convention on Narcotic Drugs, including opiates as well as synthetic substances such as meperidine and fentanyl. The term covers not only the opioids but also cocaine and many other drugs of abuse. 5. At what governing levels do drug regulations exist? How do they pertain to individual practitioners? There are three tiers of drug regulations: international, federal, and state. The regulation of professional practice in medicine, nursing, pharmacy, social work, and other professions occurs at the state, and not the federal, level. There have been a number of recent changes in state laws, because of concerns about inappropriate discipline of physicians for prescribing opioid analgesics. 6. What is the historical background that led the federal government to become involved in monitoring opioids? Twentieth-century governments recognized the dangers of abuse and trafficking of opioids, including opium, morphine, and heroin. Concerns, particularly about the opium trade in China and the Philippines, prompted governments throughout the world to join together and set controls on the ever-increasing diversion of illegal substances. Studies of addicts in the 1950s and 1960s seemed to show that many addicts had their first exposure to opioids from prescriptions during a painful illness. The finding was incorrectly extrapolated to suggest that medical treatment was a common cause of addiction. 7. What is the International Narcotics Control Board? The International Narcotics Control Board (INCB) is a Vienna-based arm of the United Nations International Drug Control Program. It monitors the implementation of the Single Convention on Narcotic Drugs, an international treaty. The INCB recommends steps that governments and health professionals should take to address this problem. 8. What do governments perceive as the major impediments to the medical use of opioids? In a survey of 65 governments performed by the INCB, concern about addiction was the most frequently stated impediment to the medical use of opioids; this concern appeared in 72% of statements. The next most frequently stated issue was insufficient training of health care practitioners. Sixty-five percent of the governments surveyed reported that they had national policies to improve the use of opioids. 9. Are legal restrictions on opioid prescriptions prevalent throughout the world? The following is a quotation from literature produced by the World Health Organization (WHO) that addresses cancer pain: The WHO has observed that physicians and pharmacists may become reluctant to prescribe or stock opioid analgesics due to strict requirements and fear of punishment. In the survey, many governments reported they required special government-issued prescription forms and other special permissions. The maximum sentence for a physician who fails to comply with prescriber requirements is 22 years in prison; the maximum fine afforded is up to 1 million dollars. Some governments reported having mandatory minimum penalties as high as 10 years in prison for such offenses. Forty-three percent of the governments required health professionals to report patients who receive opioid prescriptions.

CHAPTER 36 REGULATORY ISSUES 269 None of the regulations in the United States are as stringent as this statement indicates. The majority of U.S. legislation is aimed at avoiding diversion of drugs rather than regulating appropriate prescribing practices. 10. Which federal legislation regulates the prescribing practices of opioid analgesics? The Harrison Narcotic Act of 1914 is the hallmark legislation that marked the federal government’s interest in the prescribing and controlling of opioids. In 1961, the INCB was established to receive reports from governments about the movement of opioids and to ensure that supply and demand for opioids were in balance, hoping to prevent undersupply for legitimate purposes. All governments involved are required to furnish the INCB with statistics on an annual basis. In 1971, the Federal Comprehensive Drug Abuse Prevention and Control Act repealed all previous laws and took over the control of prescription drugs. Opioids and drugs with potential for abuse were placed into five schedules. Hill (see Bibliography) summarized the source of the government’s authority to regulate as follows: Government regulations on controlled substances are authorized by two legislative sources: (a) Health Care Practice Acts (HCPAs) including medical, nursing, pharmacy, dental, etc. which set standards of practice for the use of controlled substances and all other aspects of professional practice, and (b) Controlled Substances Acts (CSAs) which mandate how such substances are to be handled when used for medical purposes. States exert influence on health care practice through enactment of HCPAs and the evaluation of practitioners’ practices, based on standards set forth in them. Federal influence is primarily through CSAs. 11. What is the controlled substances act? The following is taken from the U.S. Drug Enforcement Administration (DEA) website (see Bibliography): The Controlled Substances Act, Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, is the legal foundation of the government’s fight against the abuse of drugs and other substances. This law is a consolidation of numerous laws regulating the manufacture and distribution of narcotics, stimulants, depressants, hallucinogens, anabolic steroids, and chemicals used in the illicit production of controlled substances. The CSA places all substances that are regulated under existing federal law into one of five schedules. This placement is based on the substance’s medicinal value, harmfulness, and potential for abuse or addiction. 12. What are the schedules into which all opioids and drugs with potential for abuse are classified? The five schedules into which all opioids and drugs are classified under the Federal Comprehensive Drug Abuse Prevention and Control Act are as follows: Schedule I—Drugs with high abuse potential and no accepted medical use. Schedule II—Drugs with a high potential for abuse and severe likelihood to produce psychic or physical dependence. Schedule II controlled substances consist of certain opioid drugs and drugs containing amphetamines or methamphetamines as the single active ingredient or in combination. Examples are opium, morphine, codeine, hydromorphone, methadone, cocaine, and oxycodone. Most drugs that are effective in the management of pain caused by cancer fall into this category. Schedule III—Drugs with a potential for abuse that is less than for that of drugs in schedules I and II. Examples are drugs containing limited quantities of certain opioids and certain nonopioid drugs. Schedule IV—Drugs with a low potential for abuse that leads only to limited physical dependence or psychological dependence relative to drugs in schedule III. Examples are chlordiazepoxide and diazepam.

270 CHAPTER 36 REGULATORY ISSUES Schedule V—Drugs with a potential for abuse that is less than that of drugs in schedule IV and consist of preparations containing moderate quantities of certain opioid drugs. Examples include antidiarrheal medications. 13. How does the federal government define an addict? Federal law defines an addict as ‘‘any individual who habitually uses any narcotic drug so as to endanger the public morals, health, safety, or welfare, or who is so far addicted to the use of narcotic drugs as to have lost the power of self-control with reference to his or her addiction.’’ This definition is somewhat vague, but publications by the DEA have made it clear that the agency’s function is not to hinder physicians from using opioid analgesics to provide pain relief. According to the medical definition of addiction, the patient must have a preoccupation with securing the drug, spend a great deal of time either using the drug or recovering from its effects, and continue to use the drug despite harmful effects. 14. What is the role of the Drug Enforcement Administration (DEA)? The Drug Enforcement Administration (DEA) is the federal agency responsible for enforcing national drug laws. It is responsible for registering manufacturers, distributors, and practitioners who handle opioid drugs. The DEA works closely with the Food and Drug Administration and the National Institute on Drug Abuse, which determines annual quotas for amounts of the various opioids that can be manufactured and distributed. 15. What is the mission of the DEA? According to the DEA website (see Bibliography): The mission of the DEA is to enforce the controlled substances laws and regulations of the United States and bring to the criminal and civil justice system of the United States, or any other competent jurisdiction, those organizations and principal member organizations, involved in the growing, manufacture, or distribution of controlled substances appearing and/or destined for illicit traffic in the United States; and to recommend and support non-enforcement programs aimed at reducing the availability of the illicit controlled substances on the domestic and international markets. 16. What have been the benefits, if any, of the federal drug control laws? Before the establishment of the international drug control system, legitimate manufacturers were the primary source of abused opioid drugs, including heroin. After 1925, legitimate production of opioids has rarely been a source of drugs in the illicit traffic. Because the federal definition of addiction is generally vague, it has not particularly limited prescribing practices. The goal of the federal laws has been to ensure that a therapeutic drug is available to patients when it is needed; laws do not restrict the size of prescriptions or set limits on refills. Many state laws, however, limit prescriptions to a 1-month supply and may even limit the number of doses. 17. What potentially detrimental perceptions have resulted from the federal drug control system? By essentially waging a ‘‘war on drugs,’’ the government may have unintentionally restricted medical access to essential medications. The drugs often necessary for managing pain in cancer and other medical illnesses are also the commonly abused drugs. This unfortunate coincidence has negatively influenced the effective treatment of pain worldwide. Regulation of drugs communicates that they are dangerous and reinforces fears. Legitimate manufacturers are concerned about production, physicians are reluctant to prescribe them, and patients are reluctant to take them for fear of being labeled addicts. Forcing physicians to register with the federal government to prescribe opioid medications has significantly curtailed their use.

CHAPTER 36 REGULATORY ISSUES 271 18. How have state laws affected prescribing practices? Although most state controlled substance laws are patterned after the Federal Uniform Controlled Substances Act, there are many important differences. Many state laws do not recognize the essential medical uses of controlled substances or the importance of ensuring availability within the state. Many state laws do not have provisions allowing opioid treatment of intractable pain. There is a great deal of confusion among physicians about what the laws really say. Nearly one fourth of physicians polled in one study felt that it was probably a violation of federal or state laws to prescribe opioids for chronic nonmalignant pain. One half of the physicians surveyed thought that prescription was illegal for patients with a history of opioid abuse. In point of fact, the law considers prescription of opioids illegal only if it is done to maintain an addiction. Methadone maintenance can be prescribed only through a methadone maintenance program. 19. Have state laws affected prescribing practices and availability of controlled substances? In the past, multiple-copy prescription programs existed in many states and resulted in statewide reductions of more than 50% in the number of prescriptions written for opioids. Physicians must purchase registered and numbered books of prescriptions from the state. Each prescription has three copies: one goes to the pharmacist, one to the office chart, and one to the state. Many state laws limit the amount of medication that can be dispensed at one time, increasing costs and number of patient visits to a physician. 20. What are more recent trends in state pain policies? In the past decade, concerns about inappropriate discipline of physicians for use of opioid analgesics for treatment of chronic pain has led to changes in state laws, medical board regulations, and guidelines. State medical boards have begun to participate in pain management workshops and have begun to adopt new guidelines to encourage improved pain management. For further information regarding the role of state medical boards, the reader is invited to view information at www.fsmb.com. 21. What are Electronic Data Transmission (EDT) programs? As a result of pain initiatives, several states have moved to Electronic Data Transmission (EDT) programs, eliminating triplicate prescriptions. Currently, California, Idaho, Illinois, Michigan, and Texas are moving toward eliminating their triplicate programs and beginning EDT programs. Hawaii, Indiana, Massachusetts, Nevada, Oklahoma, Rhode Island, Utah, West Virginia, and New York have already moved to EDT. 22. Is it permissible to use opioids for the treatment of chronic pain of noncancer origin? Yes. Opioids are the mainstay for the treatment of pain of moderate to severe intensity in patients with cancer. Under appropriate guidelines (see Chapter 34, Opioid Analgesics), they can be used for many patients with pain of noncancer origin. Even patients with a prior history of addiction can be treated, although with great care. 23. How can a practitioner avoid trouble with regulatory agencies over the prescription of opioid analgesics? Document, document, document. The chart should contain a record of a complete history and physical examination, the diagnosis, and indications for the use of opioid analgesics. It

272 CHAPTER 36 REGULATORY ISSUES should be clear that the risks and benefits have been discussed with the patient and that these risks and benefits are documented in the chart. At each visit, pain relief and side effects should be noted. Very few state investigations for opioid prescribing result in actions against a physician’s license. Those that do are almost invariably the result of unimaginably poor record keeping or clearly felonious activity. 24. What are the educational issues surrounding lack of appropriate prescribing practices? Standard physician education falls short of appropriately preparing physicians for necessary training in pain management. Even physicians who understand the pharmacokinetics and pharmacodynamics of analgesic medications tend to underprescribe them. State cancer pain initiatives are addressing the issues of education of health care providers and interaction with regulatory agencies. 25. What is the Oregon Death with Dignity Act? Why is the federal government trying to overturn it? In October 1997 Oregon became the first state in the nation to legalize physician-assisted suicide. As of this writing, the Bush administration was seeking the permission of the federal courts to overturn Oregon’s Death with Dignity Act. 26. What are the provisions of the Oregon Death with Dignity Act? Under the Oregon Death with Dignity Act, doctors must certify that a patient has an illness that leaves him or her with less than 6 months to live. The patient must be at least 18 and an Oregon resident. The patient must be deemed capable of making health care decisions independently. 27. What is the doctrine of double effect? The doctrine states that all medications have both effects and side effects. Opioid analgesics produce pain relief, but may also suppress respirations. In patients with severe pain, it is recognized that increasing doses of opioids intended to relieve pain may hasten death. If the express intent is pain relief, but death ensues, the intervention is not considered physician- assisted suicide, or euthanasia. 28. What is the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), and what does it want from us? The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) is an independent, not-for-profit organization that evaluates and accredits nearly 19,000 health care organizations and programs in the United States. It sets standards for patient evaluation, treatment, and education. Health care organizations are surveyed on a regular basis. Recently, with the help of nationally recognized pain management experts, standards for pain management were established. The standards state that pain must be evaluated in all patients; that an appropriate plan of action must be established; and that patients, families, and health care providers must be educated with regard to pain management.

CHAPTER 36 REGULATORY ISSUES 273 KEY POINTS 1. Physicians’ concerns regarding regulatory scrutiny remain a significant barrier for the effective treatment of patients’ pain. 2. Technically the term narcotic refers to drugs other than opioids, including cocaine and many other nonopioid drugs that are abused; thus, opioid is clearly the preferred term when referring to this class of analgesic medications. 3. It is permissible for an appropriately trained practitioner to prescribe opioids for both cancer as well as noncancer moderate to severe pain; when doing so the chart should contain a record of a complete history and physical examination, the diagnosis, and indications for the use of opioid analgesics. It should be clear that the risks and benefits have been discussed with the patient and that these risks and benefits are documented in the chart. At each visit, pain relief and side effects should be noted and the rationale for continuation or discontinuation of opioid therapy clearly documented. WEBSITES 1. http://www.usdoj.gov/dea/agency/mission.htm 2. http://www.medsch.wisc.edu/painpolicy/domestic/resource.htm 3. http://www.fsmb.com BIBLIOGRAPHY 1. Angarola RT, Joranson DE: Recent developments in pain management and regulation, APS Bulletin 4(1):9-11, 1994. 2. Dahl JL: State cancer pain initiatives, J Pain Symptom Manage 8(6):372-375, 1993. 3. Gilson AM, Joranson DE: Controlled substances and pain management: changes in knowledge and attitudes of state medical regulators, J Pain Symptom Manage 21(3):227-237, 2001. 4. Hill CS: Government regulation influences on opioid prescribing and their impact on the treatment of pain of nonmalignant origin, J Pain Symptom Manage 11(5):287-298, 1996. 5. International Opium Convention of 1925, League of Nations Treaties Series, Vol 81, 317: Convention of 1931 for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs, League of Nations Treaty Series 139:301, 1931. 6. Joranson DE, Gilson AM: Pharmacists’ knowledge of and attitudes toward opioid pain medications in relation to federal and state policies, J Am Pharm Assoc (Wash) 41(2):213-220, 2001. 7. Joranson DE, Gilson AM, Dahl JL, Haddox JD: Pain management, controlled substances, and state medical board policy: a decade of change, J Pain Symptom 23(2):138-147, 2002. 8. Kanner RM: How much is knowledge really worth? J Pain Symptom Manage 6(5):340-341, 1991. 9. Kanner RM: Opioids for severe pain: little change over 15 years (letter), J Pain Symptom Manage 21(2):3, 2001. 10. Max MB: Pain relief and the control of drug abuse: conflicting or complementary goals? In Hill CS Jr, Fields WS (editors): Advances in pain research and therapy, vol. 11, New York, 1989, Raven Press. 11. Steinbrook R: Physician-assisted suicide in Oregon—an uncertain future, New Engl J Med 346(6):460-464, 2002. 12. Verhovek SH: As suicide approvals rise in Oregon, half go unused, New York Times. Wysiwyg://9/http://www. nytimes.com/2002/02/07/national/07suic.html

CHAPTER 37 ADJUVANT ANALGESICS Brian Thiessen, MD, Russell K. Portenoy, MD, and Charles E. Argoff, MD 1. What are adjuvant analgesics? Adjuvant analgesics (Table 37-1) are drugs that have primary indications other than pain but are analgesic in some painful conditions. This definition distinguishes a very diverse group of drugs from the traditional analgesics, which comprise the nonopioid analgesics (acetaminophen and the nonsteroidal antiinflammatory drugs) and the opioid analgesics. :TABLE 37-1. A D J U V A N T A N A L G E S I C S M A J O R C L A S S E S Multipurpose Analgesic Agents Analgesic Agents for Analgesics for Neuropathic Pain Musculoskeletal Pain Syndromes Syndromes Antidepressants Antidepressants Muscle relaxants Alpha-2 adrenergic Anticonvulsants Benzodiazepines agonists Corticosteroids GABA agonists Analgesic agents for bone pain Topical anesthetics Oral local anesthetics Topical anesthetics Corticosteroids Sympatholytics NMDA Osteoclast inhibitors receptor blockers Calcitonin Radiopharmaceuticals GABA ¼ gamma-aminobutyric acid, NMDA ¼ N-methyl-D-aspartic acid. 2. For whom and in which situations are adjuvant analgesics appropriate? As suggested by the label ‘‘adjuvant,’’ these analgesics are often coadministered with the traditional analgesics. In some patient populations, particularly those with cancer pain, the conventional approach involves the addition of an adjuvant analgesic drug only after the dose of a traditional analgesic (usually an opioid) has been optimized. In these populations, the adjuvant analgesics are administered for the following purposes: & To manage pain that is refractory to the traditional analgesics & To allow reduction in dose of the traditional analgesic for the purpose of lessening side effects & To concurrently treat a symptom other than pain In some clinical settings, adjuvant analgesics have become so well accepted that they are administered as the first-line drug. This is particularly true for chronic neuropathic pain syndromes unrelated to cancer, such as postherpetic neuralgia, trigeminal neuralgia, or painful polyneuropathy (see Question 25). In these situations, the term adjuvant is a misnomer. 274

CHAPTER 37 ADJUVANT ANALGESICS 275 3. What factors should be considered prior to prescribing an adjuvant analgesic? The physician must be aware of the drug’s clinical pharmacology and its particular use in patients with pain. Learn the following about the analgesic: & Approved indications & Unapproved indications widely accepted in medical practice & Common side effects and uncommon, but potentially serious, adverse effects & Important pharmacokinetic features, including half-life, usual time-action relationships, extent of interindividual variability, and factors that may alter disposition (e.g., age or interactions with other drugs) & Specific dosing guidelines for pain 4. What are the special considerations for the older person? In the medically frail and the older population, a cautious approach to the use of the adjuvant analgesics is warranted. It is prudent to select a drug with a good safety profile and begin therapy at a relatively low dose. Gradual escalation of the dose is the safest technique for confirming an effective regimen or determining that the drug is ineffective. 5. Are responses to the adjuvants uniform? No. There is considerable interindividual and intraindividual variation in the response to adjuvant analgesics. This variation underscores the potential utility of sequential drug trials, which may be needed to identify a drug with a favorable benefit-to-risk ratio. Moreover, most trials benefit from the use of gradual dose escalation to identify the most optimal dose. Explain dose escalation and the potential need for multiple trials to patients who are about to begin therapy with an adjuvant analgesic. The information will help the patient maintain appropriate expectations and will reduce frustration during a period of ineffective dosing. 6. Which classes of adjuvant analgesics may be considered multipurpose, nonspecific analgesics? Adjuvant analgesics that have been demonstrated to be effective in diverse pain syndromes can be designated multipurpose analgesics. The best characterized of these drugs are the tricyclic antidepressants (TCAs). Other classes that can be considered multipurpose include the alpha-2 adrenergic agonists (e.g., clonidine) and the corticosteroids. Although there is some evidence to support the labeling of local anesthetic drugs in this way, conventional practice now limits the use of this class to patients with neuropathic pain syndromes (see next question). 7. What is the evidence that antidepressant drugs are multipurpose analgesics? Antidepressant drugs, especially the TCAs, have been extensively evaluated in many different pain syndromes, including neuropathic pain, low back pain, headache, fibromyalgia, arthritis, cancer pain, and others. They have been found to have multipurpose analgesic effects. A trial of an analgesic antidepressant is warranted in most patients with chronic pain. 8. Which antidepressants are recommended for chronic pain? The tertiary amine compound amitriptyline has been best studied, but there is evidence supporting the analgesic efficacy of other tertiary amine tricyclic drugs as well, including imipramine, clomipramine, and doxepin. Of the secondary amine tricyclic compounds, which are generally better tolerated than the tertiary amine drugs, desipramine has been most carefully studied, and nortriptyline is also probably analgesic. Compared with the tertiary amine drugs, these secondary amine compounds are less likely to produce sedative, anticholinergic, or hypotensive side effects. (However, see Question 9.) Among the newer classes of antidepressants, analgesic effects have been noted for the serotonergic noradrenergic reuptake inhibitors (SNRI) agents duloxetine, venlafaxine, and milnacipran. Duloxetine is in fact approved by the Food and Drug Administration (FDA) for diabetic peripheral neuropathic pain and fibromyalgia. Milnacipran is available in Europe but not in the United States. Analgesic effects have been suggested for bupropion, trazodone,

276 CHAPTER 37 ADJUVANT ANALGESICS maprotiline, and paroxetine, which is a selective serotonin reuptake inhibitor (SSRI). Of these newer classes, the SSRIs and SNRIs are usually better tolerated than the TCAs. 9. What is the relative analgesic efficacy of the various antidepressant classes? There have been few studies directly comparing the analgesic efficacy of the various antidepressant drugs. From the very limited data available, an analgesic response is most likely to be produced by the tertiary tricyclic drugs; amitriptyline is preferred because of the extensive data available for this drug. The secondary amine tricyclic drugs, such as desipramine, are probably less analgesic than the tertiary amine drugs, but are more likely to be effective than the SSRIs. But SSRIs have fewer side effects than either secondary or tertiary amines (Table 37-2). Based on this information, the clinician should attempt to select the drug most likely to provide benefit and be tolerated by the patient. TABLE 37-2. C O M P A R I S O N O F A N T I D E P R E S S A N T S I D E E F F E C T S Somnolence Cardiotoxicity Anticholinergic Tertiary amines þþ þþþ þþþ Amitriptyline þ þþ þ Secondary amines þ/À À À Nortriptyline Desipramine SSRIs Paroxetine SSRI ¼ selective serotonin reuptake inhibitors. 10. Do the monoamine oxidase inhibitors have analgesic effects? The monoamine oxidase inhibitors (MAOIs), such as phenelzine and tranylcypromine, have been evaluated as analgesics in relatively few clinical settings. In a controlled trial, phenelzine was analgesic in patients with atypical facial pain, and a few uncontrolled trials suggested analgesic properties in other types of chronic pain. Despite these findings, use of MAOIs as analgesics has been limited because of the risk of hypertensive crises and the need for significant dietary restrictions. 11. True or false: Relief of depression and analgesia are codependent. False. Relief of depression is not required for the analgesia produced by antidepressant drugs, although improvement in mood no doubt plays a role in some patients. The analgesia produced by the TCAs occurs at a dose significantly lower than that required to treat depression and usually appears within 1 week after this dose is reached—much sooner than the antidepressant effects typically appear. 12. What mechanisms may be responsible for antidepressant analgesia? The primary pharmacologic action of the antidepressants is to block reuptake of monoaminergic neurotransmitters (e.g., serotonin and norepinephrine) in the central nervous system. Descending pain modulatory pathways that use serotonin and norepinephrine as neurotransmitters have been well characterized, and altered activity in these pathways could be the mechanism by which these drugs yield analgesic effects. The TCAs also interact with many other receptors, some of which have been implicated in other pain-modulating systems. Interestingly, recent studies have shown that the SSRIs do not yield as much analgesia as the TCAs in patients who are not depressed. The so-called dirty drugs (those affecting multiple receptors, such as TCAs) may exert their effects through multiple systems.

CHAPTER 37 ADJUVANT ANALGESICS 277 13. What are the adverse effects of the antidepressants? The secondary amine TCAs are less toxic than the tertiary amine compounds, and the SNRIs and SSRIs are less toxic than either tricyclic subclass (see Table 37-2). At doses commonly used for pain control, the tricyclic compounds have few serious adverse effects. Cardiovascular toxicity, including hypotension and cardiac arrhythmia, is the most serious concern. Significant heart disease, including conduction disturbances, arrhythmias, or heart failure, is a relative contraindication to treatment. Secondary amine compounds, SNRIs, and SSRIs have a lower incidence of cardiotoxicity and are preferred if cardiac disease is present. The more common side effects of the TCAs are less serious. Anticholinergic effects include dry mouth, urinary retention, blurred vision, and constipation. Somnolence and mental clouding are often transient but are a particular problem in the older person. Nausea is usually the most common side effect of the SSRIs. Some patients report tremulousness or insomnia, and some experience somnolence. Sexual dysfunction can be a problem for others. 14. Do any particular characteristics among patients suggest a trial of an antidepressant analgesic? A trial of an antidepressant analgesic is potentially appropriate for any type of chronic pain. The presence of a psychiatric disorder that may also respond to these drugs, such as major depression or panic disorder, suggests an early trial. Insomnia may justify an early trial of an antidepressant analgesic, such as amitriptyline, which has sedating properties. When the antidepressants are used to treat chronic neuropathic pain (see Question 26), they are often considered first-line drugs for the management of pain characterized by continuous dysesthesias. These dysesthesias are often described by patients as burning, electrical, or painful numbness. Although lancinating (stabbing) neuropathic pain can respond, antidepressants are not usually considered first-line drugs for pain of this type. In the management of cancer pain, the usual indication for a trial of an antidepressant is chronic neuropathic pain that has not responded adequately to opioid analgesics. In this setting, these drugs are used as adjuncts to an optimized opioid regimen. 15. A healthy 70-year-old man is beginning therapy with amitriptyline for painful neuropathy. What is an appropriate starting dose and dosing schedule? The starting dose of any tricyclic agent should be low, especially in the older person. For example, the recommended initial dose for amitriptyline is 10 mg/day in the older person and 25 mg/day in younger patients. The dosage can be gradually increased every 2 to 3 days until an effective dose is reached. For amitriptyline and desipramine, the effective dose is usually 50 to 150 mg/day. Blood levels can help guide therapy. The tricyclic drugs are usually administered as a single nighttime dose, thereby allowing sedative effects to occur while the patient is asleep. Some patients, however, experience a morning ‘‘hangover’’ and respond better to divided doses. The inability to tolerate a trial of amitriptyline or the existence of relative contraindications to this drug (such as preexisting cognitive impairment, prostatism, constipation, or dry mouth) might be addressed by a trial of a secondary amine tricyclic, such as desipramine. If the risks associated with a TCA are too high, consider a trial of an SSRI, such as paroxetine. 16. What role do tizanidine and clonidine have as adjuvant analgesics? Alpha-2 adrenergic agonists can be multipurpose, nonspecific analgesics; tizanidine and clonidine are used for this purpose in the United States. Although one study suggests that only a small proportion of patients with chronic pain respond to clonidine, responders may attain excellent analgesia. Clonidine has been shown to be analgesic in chronic headache, chronic neuropathic and nonneuropathic noncancer pain syndromes, and cancer-related neuropathic pain. Because of limited experience, clonidine is not generally considered a first-line drug, but it may be used in refractory cases. Clonidine is actually FDA-approved when epidurally administered for the treatment of cancer-associated neuropathic pain. The major side effects are dry mouth and sedation. Hypotension may occur, and these drugs must be used cautiously in patients predisposed to this effect. Tizanidine is less likely than clonidine to cause hypotension.

278 CHAPTER 37 ADJUVANT ANALGESICS 17. What is the mechanism of analgesia produced by alpha-2 adrenergic agonists? The mechanism or mechanisms that produce analgesia are unknown. Noradrenergic pain- modulating systems exist in the central nervous system, and it is possible that the alpha-2 adrenergic receptor is involved in the functioning of this pathway. Activation of the alpha-2 receptor inhibits the release of norepinephrine. Central sympathetic inhibition may be the analgesic mechanism involved in those pain syndromes sustained, at least in part, by sympathetic efferent activity (so-called sympathetically maintained pain). 18. What is the role of neuroleptic drugs in the treatment of pain? The role of neuroleptic drugs in the treatment of pain is quite limited. Methotrimeprazine is a phenothiazine neuroleptic that was demonstrated to be a multipurpose analgesic. The drug is no longer available. Although the experience with methotrimeprazine suggested that neuroleptic drugs can be nonspecific analgesics, there is actually very little evidence that other drugs in the class have analgesic effects. Anecdotal reports have suggested that drugs such as haloperidol or fluphenazine may be analgesic in neuropathic pain, and, on this basis, a therapeutic trial of one of these drugs is sometimes administered in cases of neuropathic pain and pain that has been refractory to other therapies. As yet, there is no good evidence that the newer neuroleptics, such as olanzapine, are effective analgesics. In migraine headache, a number of trials have shown efficacy for parenterally administered chlorpromazine and droperidol. Some of the success may have been due to antinauseant effects. 19. Describe the extrapyramidal side effects of neuroleptics. The extrapyramidal effects of neuroleptics can be divided into two groups: those that occur early in the course of treatment and those that are delayed in onset. The early effects include acute dystonic reactions (such as torticollis), parkinsonism, akathisia, and neuroleptic malignant syndrome. The late effects include tardive dyskinesia and other tardive movement disorders. The ability to produce extrapyramidal syndromes is directly related to the potency of the antipsychotic, whereas the anticholinergic effects are inversely related to potency. Therefore, haloperidol is more likely to produce extrapyramidal effects and less likely to produce orthostatic hypotension than is chlorpromazine. Other side effects include sedation, orthostatic hypotension, and anticholinergic effects such as dry mouth, blurred vision, and urinary hesitancy. Mental clouding and confusion are relatively common in the older and medically ill patients. Rarely, neuroleptics may cause idiosyncratic side effects such as skin rashes, blood dyscrasias, and hepatic damage. 20. List some of the common pain syndromes for which corticosteroids have shown benefit. In the noncancer pain population, short courses of corticosteroids are often given to provide symptomatic relief of acute herpetic neuralgia, carpal tunnel syndrome, and reflex sympathetic dystrophy. Long-term therapy is avoided because of the risk of toxicity. Epidural administration of corticosteroids may be beneficial for some patients with acute exacerbations of low back pain. Local injections of corticosteroids are also used for carpal tunnel syndrome and acute bursitis. In the cancer population, the use of these drugs is far more extensive. Controlled trials and clinical series have shown that corticosteroids can be beneficial in many types of cancer pain, including malignant epidural spinal cord compression, bone pain, pain caused by increased intracranial pressure, neuropathic pain from compression or infiltration of peripheral neural structures, and pain from expansion of visceral capsules or obstruction of a hollow viscus. 21. Which corticosteroid is the agent of choice in patients with cancer? Dexamethasone is the preferred corticosteroid in the cancer population. Use is justified by the low mineralocorticoid effects produced by this drug.

CHAPTER 37 ADJUVANT ANALGESICS 279 22. How do corticosteroids produce analgesia? It is likely that corticosteroids have a variety of analgesic mechanisms. Corticosteroids have direct antiinflammatory effects, reducing the tissue concentrations of inflammatory mediators that activate nociceptors. They also reduce the aberrant firing that can originate from sites of nerve injury. Pain related to malignant compression may lessen because of steroid-induced reduction of peritumoral edema and, in cases of steroid-responsive neoplasms, reduction of tumor bulk. 23. List the common side effects associated with corticosteroid use. Acute treatment with corticosteroids is usually well tolerated. Potential toxicities include hyperglycemia, fluid retention (which may cause hypertension or cardiac failure in predisposed patients), dyspepsia, peptic ulcer disease, insomnia, and neuropsychological effects (ranging from frank delirium to isolated mood or cognitive or perceptual disturbances). Chronic administration of corticosteroids can cause the following adverse effects: cushingoid habitus, weight gain, hypertension, osteoporosis, myopathy, increased risk of infection, hyperglycemia, and peptic ulcer disease. Rarely, chronic treatment results in aseptic necrosis of the femoral or humeral head. 24. What dosing regimens are commonly used when corticosteroids are administered for pain? When corticosteroids are administered for pain, dosing regimens are divided into low-dose and high-dose schemes. A high-dose regimen in cancer is most commonly a 100-mg loading dose of dexamethasone followed by 24 mg every 6 hours. It is often initiated in the setting of very severe, often rapidly escalating pain (‘‘crescendo pain’’) that has not responded promptly to an opioid. Severe bone pain and worsening malignant plexopathy are examples of such pain syndromes. In addition, oncologic emergencies that are steroid-responsive, such as superior vena cava syndrome and malignant epidural spinal cord compression, are commonly managed with high-dose steroid regimens. Low-dose dexamethasone regimens vary from 4 mg every 6 hours to 1 to 2 mg twice daily. They are commonly used in the setting of advanced medical illness with pain refractory to opioids and other adjuvant agents. Given the side effects of these agents, the patient must be continually assessed for efficacy and toxicity during long-term therapy. In all cases, the lowest dose that achieves the desired analgesic benefit should be sought. Other corticosteroids, including prednisone and methylprednisone, have also been used as analgesics. There have been no comparative trials of the various drugs, and the doses that have been administered have varied. 25. What is neuropathic pain? Neuropathic pain describes a diverse set of pain syndromes in which the sustaining mechanism is believed to involve aberrant somatosensory processing in the peripheral or central nervous system. The term includes syndromes such as painful polyneuropathy, trigeminal neuralgia, central pain, postherpetic neuralgia, and phantom pain. 26. What is the role of the adjuvant analgesics in the treatment of chronic neuropathic pain? Neuropathic pain syndromes are often refractory to traditional analgesics. Thus the adjuvant analgesics are extremely valuable for these diverse disorders. Although data from clinical trials are inadequate to guide the selection of specific drugs, some general guidelines can be recommended on the basis of clinical experience. Patients with neuropathic pain characterized by continuous dysesthesias (often described as constant burning or electrical sensations) are usually offered an anticonvulsant or antidepressant analgesic early (Table 37-3). Orally administered local anesthetics are also commonly used, and other multipurpose analgesics (such as tizanidine or clonidine) may be considered in refractory cases.

280 CHAPTER 37 ADJUVANT ANALGESICS TABLE 37-3. A D J U V A N T A N A L G E S I C S T Y P I C A L L Y S E L E C T E D F O R N E U R O P A T H I C PAIN WITH PREDOMINATING CONTINUOUS DYSESTHESIAS First Line Examples Anticonvulsants Gabapentin, carbamazepine, valproate, clonazepam, pregabalin, others Tricyclic antidepressants Amitriptyline, desipramine ‘‘Newer’’ antidepressants Paroxetine, duloxetine Oral local anesthetics Mexiletine, tocainide, flecainide For Refractory Cases Alpha-2 adrenergic agonists Clonidine, tizanidine Topical agents Capsaicin, local anesthetics NMDA receptor antagonists Dextromethorphan, ketamine Calcitonin Baclofen NMDA ¼ N-methyl-D-aspartic acid. Patients with lancinating (stabbing) pain or neuropathic pain characterized by a paroxysmal onset and longer duration are usually first offered trials of anticonvulsants or baclofen, a gamma-aminobutyric acid agonist (Table 37-4). Trials with the drugs used for continuous neuropathic pain usually follow. Finally, patients suspected of having neuropathic pain sustained by efferent activity in the sympathetic nervous system (sympathetically maintained pain) are sometimes treated with adjuvant analgesics that may modulate sympathetic function. TABLE 37-4. A D J U V A N T A N A L G E S I C S T Y P I C A L L Y S E L E C T E D F O R N E U R O P A T H I C PAIN WITH PREDOMINATING LANCINATING OR PAROXYSMAL DYSESTHESIAS First Line Examples Anticonvulsants Gabapentin, carbamazepine, valproate, clonazepam, Baclofen pregabalin, others For Refractory Cases Oral local anesthetics Mexiletine, tocainide, flecainide Tricyclic antidepressants Amitriptyline, desipramine Newer antidepressant Paroxetine, duloxetine Alpha-2 adrenergic agonists Clonidine, tizanidine Topical agents Capsaicin, local anesthetics NMDA receptor antagonists Dextromethorphan, ketamine Calcitonin NMDA ¼ N-methyl-D-aspartic acid.

CHAPTER 37 ADJUVANT ANALGESICS 281 27. How are anticonvulsants used in the management of neuropathic pain? Abundant survey data and controlled studies have established the efficacy of anticonvulsant drugs for neuropathic pain (see Table 37-4). Gabapentin and pregabalin are most widely used for this indication, but other anticonvulsants, including phenytoin, carbamazepine, valproate, and clonazepam, have been used for many years. Gabapentin and pregabalin are useful in diabetic peripheral neuropathy and postherpetic neuralgia. Each appears to have a favorable safety profile. Other anticonvulsants that are used for neuropathic pain include lamotrigine, topiramate, tiagabine, oxcarbazepine, and zonisamide. In general, the anticonvulsants should be started at a low dose and titrated gradually. 28. List some painful conditions with prominent lancinating or paroxysmal symptoms for which the anticonvulsant agents have shown benefit. Trigeminal neuralgia was the first painful condition for which the analgesic benefit of carbamazepine was described. Other anticonvulsants have also been used to treat this condition. Studies have demonstrated the efficacy of these drugs in the treatment of lancinating pain associated with postherpetic neuralgia and painful diabetic neuropathy. Other reports suggest benefit in glossopharyngeal neuralgia, tabetic lightning pains, paroxysmal symptoms of multiple sclerosis, stabbing pain following laminectomy, lancinating pain caused by cancer, and posttraumatic mononeuropathy. 29. Can anticonvulsants be used for continuous dysesthesias? Although many practitioners believe that anticonvulsants are most efficacious for lancinating pain, studies have indicated that patients with continuous dysesthesias, such as the constant burning reported by many patients with painful polyneuropathy, do experience relief from anticonvulsant drugs (see Table 37-3). 30. What are the adverse effects associated with carbamazepine? Of all the analgesic anticonvulsants, carbamazepine has been most widely used. Other anticonvulsants are less likely to cause side effects, however. Carbamazepine commonly causes sedation, dizziness, diplopia, unsteadiness, and nausea. These effects can be minimized by starting with low initial doses (100 mg, two or three times per day) and increasing the dose gradually (by 100 mg every other day). The effective analgesic dose is variable, and dosing should be increased until pain is relieved, side effects occur, or the plasma concentrations exceed the therapeutic range for seizure control. Carbamazepine often lowers white blood cell counts, but clinically significant leukopenia or thrombocytopenia occurs rarely. A complete blood count should be obtained prior to therapy, several weeks later, and then 2 or 3 months after that. Therapy should be discontinued if a serious decline in blood count (e.g., a leukocyte count below 3000/ml) occurs. Hepatotoxicity is also rare with carbamazepine, but the possibility dictates periodic monitoring of liver function tests. Hyponatremia resulting from inappropriate secretion of antidiuretic hormone is an uncommon and usually asymptomatic adverse effect. Hypersensitivity reactions, usually rash, occur rarely. Cases of Stevens-Johnson syndrome have been reported. 31. Is there much individual variation in the response to drugs used for the management of lancinating or paroxysmal dysesthesias? Yes. Patients with lancinating or paroxysmal dysesthesias may respond to one anticonvulsant but not to others, or they may not respond to any of the anticonvulsants but do well with one of the other drugs used to treat pain of this type (see Question 32). For this reason, it is appropriate to undertake sequential trials of anticonvulsant drugs in patients with refractory pain.

282 CHAPTER 37 ADJUVANT ANALGESICS 32. What other drugs are used in the management of lancinating or paroxysmal dysesthesias? Baclofen, a gamma-aminobutyric acid-B receptor agonist, is generally considered the best alternative to the anticonvulsants in the treatment of lancinating or paroxysmal dysesthesias, including trigeminal neuralgia. Treatment is usually started at 5 mg three times per day and slowly increased to the range of 30 to 90 mg/day. Baclofen must not be withdrawn abruptly, as this can precipitate a withdrawal syndrome characterized by restlessness, delirium, and seizures. Many other drugs have also been used to treat refractory lancinating neuropathic pain. Orally administered local anesthetics are often selected if an anticonvulsant and baclofen have failed. A butyrophenone neuroleptic, pimozide, has been shown to be effective for trigeminal neuralgia and has been used for similar pains. This drug has a high side-effect profile, however, and is often poorly tolerated. Other drugs, including antidepressants (e.g., amitriptyline) and agents usually selected for neuropathic pains of other types, are also used in this setting. 33. What is the role of systemically administered local anesthetics in the treatment of neuropathic pain? Systemically delivered local anesthetics have been used to treat both acute and chronic pain for many years. Brief intravenous infusions of lidocaine or procaine can potentially relieve diverse types of pain, including those not categorized as neuropathic. The need for careful monitoring during this therapy and uncertainty about the optimal dosing guidelines and durability of effects have limited its utility. Treatment with systemic local anesthetics has become commonplace with the advent of oral local anesthetic drugs, such as mexiletine, tocainide, and flecainide. The use of these drugs has focused on neuropathic pain because of evidence of efficacy from several controlled trials in painful polyneuropathy and painful traumatic mononeuropathy. A trial of an oral local anesthetic is usually recommended in patients without medical contraindications who have continuous dysesthesias that have been refractory to antidepressant treatment, and in those with lancinating neuropathic pain that has not responded to anticonvulsants or baclofen. In the United States, mexiletine is the preferred drug for this indication. 34. What are the relative contraindications to the use of oral local anesthetic agents? Cardiovascular toxicity is a major concern when using oral local anesthetic agents. Toxic concentrations of systemically delivered local anesthetics can produce cardiac conduction disturbances and myocardial depression. Patients with a history of cardiac failure or arrhythmia and those at risk for these problems (e.g., patients with known coronary artery disease) should not receive these drugs without an appropriate evaluation. Referral to a cardiologist may be required. 35. When using oral local anesthetic agents, how should you monitor the potential for cardiovascular toxicity? Most patients older than 50 and all those with known heart disease should be monitored with repeated electrocardiograms (ECG) during dose escalation of oral local anesthetic agents. Younger patients with no known cardiac disease should also undergo an ECG if relatively high doses are reached. The first sign of local anesthetic toxicity is prolongation of the PR interval and QRS duration. With higher concentrations, bradycardia and arrhythmias occur. Additional toxicities include dizziness, perioral numbness, encephalopathy, and seizures. Nausea and vomiting are common with mexiletine. Liver damage and blood dyscrasias are rare complications.

CHAPTER 37 ADJUVANT ANALGESICS 283 36. What is the role of topical drugs in the treatment of pain? Three types of topical drugs have been used in the management of chronic pain: local anesthetics, capsaicin, and nonsteroidal antiinflammatory drugs. Although these drugs are most often used in the treatment of neuropathic pains, they are sometimes used in other syndromes as well. A trial of a topical local anesthetic is often considered for neuropathic pain syndromes characterized by a predominant peripheral mechanism and continuous dysesthesias and for nonneuropathic pain syndromes attributable to a focus of cutaneous or subcutaneous tissue injury. A lidocaine-impregnated patch is approved in the United States for treatment of postherpetic neuralgia and can be tried in other conditions. 37. Which topical local anesthetic produces cutaneous anesthesia? Only one commercially available formulation can produce dense cutaneous anesthesia: a 1:1 mixture of lidocaine and prilocaine known as a eutectic mixture of local anesthetics (EMLA). This drug, which is approved for the prevention of pain caused by needle punctures, was shown to be beneficial in a limited study of patients with postherpetic neuralgia and has been used to treat a variety of chronic pain syndromes. Cutaneous anesthesia is produced if the cream is applied in a thick layer and covered with an occlusive dressing for at least 1 hour. The need for cutaneous anesthesia for pain relief has not been established in all syndromes, however, and it is possible that some patients will respond to a thin application of EMLA without a dressing, or to other commercially available topical anesthetic preparations that do not produce cutaneous anesthesia. Therefore, patients who are offered a trial with EMLA should be encouraged to try different modes of application. If an occlusive dressing is needed and a large area of skin must be covered, ordinary plastic wrap often suffices. 38. How is topical capsaicin used in the treatment of chronic pain? Capsaicin, an ingredient in hot peppers, is known to deplete small peptides in primary afferent neurons, including those involved in pain transmission. For example, this compound releases and then depletes the peptide known as substance P, which mediates pain transmission at the first central synapse in the dorsal horn of the spinal cord. The evidence suggests that some patients with neuropathic pain will benefit from the topical application of this drug to the painful site. Several controlled trials indicate that patients with painful arthritic small joints can also benefit from the topical application of this drug. 39. Discuss the method of application of capsaicin. Capsaicin cream is commercially available in 0.025% and 0.075% concentrations. The higher concentration has been tested most often in clinical trials and in most instances should be tried first. The cream is applied locally to the painful region three to four times per day. A minimum 4-week trial is necessary to obtain maximal benefit. The major adverse effect is local burning, which can be intense and necessitate discontinuation of the cream. Initial burning may diminish with repeated applications. Alternatively, applying a topical local anesthetic or ingesting an analgesic prior to application of the capsaicin may allow continuation of the therapy. 40. Are topical nonsteroidal antiinflammatory drugs effective? There is evidence that topical nonsteroidal antiinflammatory drugs can reduce musculoskeletal pain. Such a formulation is sometimes administered for arthritis and other painful disorders. 41. What is sympathetically maintained pain? How is it diagnosed? Sympathetically maintained pain is a form of neuropathic pain in which the pain is believed to be sustained through efferent sympathetic activity. The diagnosis is usually suspected when patients fulfill criteria for reflex sympathetic dystrophy or causalgia. The latter two syndromes, which have recently been renamed by the International Association for the Study of Pain as complex regional pain syndrome (CRPS) types I and II, are characterized by the association of pain and local autonomic dysregulation and/or trophic changes. This constellation of findings

284 CHAPTER 37 ADJUVANT ANALGESICS raises the possibility of sympathetically maintained pain, which could potentially be ameliorated by interruption of sympathetic outflow to the painful site. Sympathetic interruption is usually accomplished by sympathetic nerve blocks. This procedure can be both diagnostic and therapeutic. (See Chapter 28, Neuropathic Pain). 42. When is drug therapy appropriate for complex regional pain syndrome? Which adjuvant agents are useful for the treatment of sympathetically maintained pain? Drug therapy is usually considered for patients with CRPS type I or II who are not candidates for sympathetic nerve blocks or who have had unsuccessful blocks. Anecdotal reports have described the use of virtually all of the multipurpose analgesics and the adjuvant analgesics for neuropathic pain. Although the mechanism of action is unknown, a trial of intranasal calcitonin is often administered on the basis of a successful controlled trial. Several drugs modulate the activity of the sympathetic nervous system and have also been used anecdotally for the diagnosis or treatment of sympathetically maintained pain. Intravenous phentolamine, an alpha-1 adrenergic antagonist, has been touted as a diagnostic test for sympathetically maintained pain, and anecdotal reports have suggested the efficacy of other adrenergic drugs. 43. Do benzodiazepine medications have a role to play as adjuvant analgesics? As previously mentioned, the anticonvulsant benzodiazepine clonazepam is used as an adjuvant analgesic, typically in the treatment of lancinating or paroxysmal neuropathic pain syndromes. Apart from this drug, however, the evidence for benzodiazepine analgesia is limited and often contradictory. Although a survey suggested that alprazolam, a benzodiazepine with antidepressant activity, is efficacious for chronic neuropathic pain in the cancer population, other benzodiazepines have not shown similar analgesic properties. Despite the limited supporting data, the benzodiazepines may have a role in the management of some pain syndromes. Patients with pain associated with anxiety disorders may report less discomfort if the anxious mood can be improved. In addition, benzodiazepines such as diazepam and lorazepam have been used to lessen muscle spasm and may be helpful in patients whose pain is related to spasm or spasticity. 44. What is the role of the so-called muscle-relaxant drugs? Musculoskeletal pain syndromes are among the most common ailments encountered in medical practice. Many of these conditions can be managed with nonpharmacological approaches. Muscle relaxants represent a diverse group, which includes antihistamines (e.g., orphenadrine), chemicals similar in structure to tricyclic compounds (e.g., cyclobenzaprine), and drugs of other structures (e.g., methocarbamol, carisoprodol, chlorzoxazone). Although each of these drugs has been demonstrated in controlled trials to offer analgesic effects in musculoskeletal pain, there is no evidence that they actually relax skeletal muscle. Nonetheless, these drugs are analgesic and are generally well tolerated. Sedation is the major side effect. They are usually used on a short-term basis and, like the benzodiazepines and opioids, should not be prescribed over a long period unless patients are carefully monitored by experienced clinicians. 45. Which adjuvant analgesics are used in the management of cancer pain? As noted, patients with neuropathic cancer pain are offered trials of the same adjuvant analgesics used to manage nonmalignant neuropathic pain syndromes. Other adjuvant analgesics may be useful in other cancer pain syndromes. The most important of these are adjuvant analgesics for the treatment of malignant bone pain or pain caused by bowel obstruction. 46. Discuss the analgesic potential of calcitonin. The effects on bone produced by calcitonin may yield analgesia in malignant bone pain and other painful conditions of bone, such as osteoporosis. This drug also has analgesic potential

CHAPTER 37 ADJUVANT ANALGESICS 285 beyond these indications. Clinical trials have shown efficacy in the treatment of sympathetically maintained pain and phantom limb pain, suggesting a possible role for this agent in patients with diverse types of refractory neuropathic pain syndromes. The mechanisms that account for analgesia in the latter conditions are unknown. 47. What is the role of psychostimulants in pain management? The main role for psychostimulants in pain management is to ‘‘open the therapeutic window’’ for opioids. In those patients in whom excessive sedation is limiting the physician’s ability to increase doses of opioids, small doses of psychostimulants, such as dextroamphetamine, may reverse sedation sufficiently to allow for higher doses and better analgesia. In postoperative pain and in headaches, caffeine has been shown to potentiate opioid analgesia. 48. How are radiopharmaceuticals used in the treatment of bone pain? Radiopharmaceuticals are radionuclide compounds that have preferential uptake into bone and thereby deliver a concentrated dose of radiation to bony metastases. Phosphorus-32 orthophosphate was the initial compound used in treating pain from bony metastases. Although it relieved bone pain in up to 80% of patients, it had a tendency to produce significant bone-marrow suppression. Of the newly developed radiopharmaceuticals, strontium-89 and samarium-153 are commercially available in the United States. Some degree of pain relief occurs in approximately 80% of patients receiving strontium-89; 10% achieve complete relief. Onset of action occurs 7 to 21 days postinjection, and the duration of action is typically 3 to 6 months. Bone marrow suppression is the major toxicity, occurring in 30% of patients. KEY POINTS 1. Adjuvant analgesics are drugs that have primary indications other than pain but are analgesic in various painful conditions. 2. Antidepressants and anticonvulsants are the most widely used adjuvant analgesic medications. 3. Knowledge of the adverse effects of the various adjuvant medications used as analgesics is essential for safe prescribing. BIBLIOGRAPHY 1. Backonja M: Anticonvulsants (antineuropathics) for neuropathic pain syndromes, Clin J Pain 16 (Suppl 2): 67-72, 2000. 2. Breitbart W: Psychotropic adjuvant analgesics for pain in cancer and AIDS, Psychooncology 7(4):333-345, 1998. 3. Cherny NI, Portenoy RK: Cancer pain: principles of assessment and syndromes. In Wall PD, Melzack R (editors): Textbook of pain, 3rd ed, Edinburgh, 1994, Churchill Livingstone, pp 787-823. 4. Fromm GH: Baclofen as an adjuvant analgesic, J Pain Symptom Manage 9:500-509, 1994. 5. Galluzzi KE: Managing neuropathic pain, J Am Osteopath Assoc 107(10, Suppl 6):ES39-48, 2007. 6. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S: Duloxetine vs. placebo in patients with painful diabetic neuropathy, Pain 116(1-2):109-118, 2005. 7. Hegarty A, Portenoy RK: Pharmacotherapy of neuropathic pain, Semin Neurol 14:213-224, 1994. 8. Holmes RA: Radiopharmaceuticals in clinical trials, Semin Oncol 20:22-26, 1993.

286 CHAPTER 37 ADJUVANT ANALGESICS 9. Monks R: Psychotropic drugs. In Wall PD, Melzack R (editors): Textbook of pain, 3rd ed, 1994, Edinburgh, Churchill Livingstone, pp 963-990. 10. Onghena P, Van Houdenhove B: Antidepressant-induced analgesia in chronic nonmalignant pain: a meta- analysis of 39 placebo-controlled studies, Pain 49:205-219, 1992. 11. Patt RB, Proper G, Reddy S: The neuroleptics as adjuvant analgesics, J Pain Symptom Manage 9:446-453, 1994. 12. Rowbotham MC: Topical analgesic agents. In Fields HL, Liebeskind JC (editors): Pharmacological approaches to the treatment of chronic pain, Seattle, 1994, IASP Press, pp 211-229. 13. Watanabe S, Bruera E: Corticosteroids as adjuvant analgesics, J Pain Symptom Manage 9:442-445, 1994. 14. Watson CP: The treatment of neuropathic pain: antidepressants and opioids, Clin J Pain 16(Suppl 2):49-55, 2000.

VIII. NONPHARMACOLOGIC MANAGEMENT CHAPTER 38 TEMPORARY NEURAL BLOCKADE Michael M. Hanania, MD, Martin R. Boorin, DMD, and Charles E. Argoff, MD 1. Describe the role of temporary nerve blocks in pain management. Nerve blocks can help in the diagnosis and treatment of pain. Peripheral and central nerve blocks help to localize the origin of the specific pain problem. When pain seems to cover multiple dermatomes, a selective peripheral nerve block helps to diagnose which nerve or dermatome is primarily responsible for the pain. Temporary nerve blocks are also necessary before more permanent neurolytic procedures can be attempted. When a permanent neurolytic procedure is contemplated, a temporary nerve block should produce significant pain relief before the longer-lasting block is instituted. For unclear reasons, a temporary nerve block sometimes results in prolonged pain relief, outlasting the duration of the local anesthetic. In cases of somatic pain, such as mechanical low back pain, temporary nerve blocks may break the pain cycle and allow increased function. This helps to facilitate physical therapy and rehabilitation, thereby preventing disuse muscle atrophy and joint dysfunction. In some syndromes (such as nerve injury) it is unclear whether the primary pain generator is peripheral (at the site of nerve injury) or central (within the spinal cord). If peripheral nerve block produces complete pain relief, it is inferred that the generator is peripheral. 2. What is the mechanism of action of local anesthesia? What are the implications for differential blockade? Local anesthetics are weak bases that reversibly block sodium channels and impair the propagation of an action potential along a nerve fiber. In general, thinner fibers are more sensitive to anesthetic blockade than thicker fibers. Unmyelinated fibers are more sensitive than myelinated fibers. Sympathetic fibers are very thin. Nociceptors (which are responsible for the perception of noxious stimuli) are A-delta fibers and C fibers (also quite thin, although somewhat thicker than the sympathetic nerves). Fibers subserving proprioception and light touch are relatively thick; motor fibers are the thickest. Thus, when progressively increasing concentrations of an anesthetic are used, sympathetic fibers are blocked first, followed by nociceptors, proprioceptors, and motor fibers. Function returns in the opposite order as anesthetics wear off. 3. Which are the ester and amide local anesthetics? Discuss their fundamental differences. The ester local anesthetics have an ester linkage between the aromatic moiety and amine group and are metabolized by plasma cholinesterases. Their half-lives in the circulation are short. A product of their metabolism is p-aminobenzoic acid, which is sometimes associated with hypersensitivity reactions. Procaine, cocaine, chloroprocaine, and tetracaine are ester anesthetics. The amide local anesthetics have an amide linkage and undergo primarily hepatic metabolism. They include lidocaine, mepivacaine, bupivacaine, levobupivacaine, ropivacaine, and etidocaine. Levobupivacaine and ropivacaine are relatively new local anesthetics that produce more sensory than motor blockade and have a lower cardiotoxicity profile bit otherwise have features that are identical to bupivacaine. 287

288 CHAPTER 38 TEMPORARY NEURAL BLOCKADE 4. What are the differences in duration of action among the commonly used local anesthetics? Duration of action of the local anesthetics depends on a number of factors including the agent in question, the vascularity of the tissue into which it is injected, and, with some of the local anesthetics, the coadministration of epinephrine. Therefore, lidocaine has a shorter duration of action than bupivacaine, levobupivacaine, and ropivacaine. Topical applications to mucous membrane (which has a high vascularity) are associated with shorter anesthesia than injection into, for example, muscle. Coadministration of epinephrine (a vasoconstrictor) prolongs the duration of action of lidocaine (a vasodilator), but has no effect on the duration of action of bupivacaine, levobupivacaine or ropivacaine (which have no significant effect on vascular tone). In addition to prolonging the action of lidocaine, epinephrine increases the maximum dose of lidocaine that can be used before toxic symptoms arise. The concentration of local anesthetic used does not significantly alter the duration of action. 5. List the toxic dose limits for peripheral nerve blockade for lidocaine and bupivacaine. Overdoses of lidocaine and bupivacaine usually produce symptoms indicative of central nervous system dysfunction (dizziness, tinnitus, metallic taste, slurred speech, and seizures). These are often followed by cardiovascular symptoms, such as hypotension, tachyarrhythmias or bradyarrhythmias, ventricular fibrillation, and, in extreme cases, electrical standstill. Toxic doses are dependent on the site of injection, with increasing risks of a toxic, as opposed to anaphylactic, reaction with injection into highly vascular tissue. Approximate maximum dose limits are as follows: Lidocaine 2-3 mg KgÀ1 Lidocaine with epinephrine 6-7 mg KgÀ1 Bupivicaine 2-3 mg KgÀ1 Bupivicaine with epinephrine 2-3 mg KgÀ1 Remember that epinephrine should not be added to a local anesthetic where it is to be injected in the territory of an end artery (e.g., digital or penile nerve block). 6. What is the role of neuraxial block in pain management? Epidural or spinal blocks provide temporary block of neural function at a spinal cord level. They help to differentiate a peripheral from a central origin of pain. If a peripheral nerve or root block has failed but a spinal block relieves pain, it may be inferred that the origin of the pain is more central (within the spinal cord), provided that the operator is confident that the nerve block has actually been achieved. Epidural blockade also offers the option of leaving the catheter in place for prolonged treatment. Thus, epidural analgesia or anesthesia can be provided on an ongoing basis or through intermittent boluses. This procedure may facilitate rehabilitation. The use of neuraxial block, while well established in acute pain management and anesthetic practice, is not supported by conclusive evidence in the field of chronic pain management. 7. List the possible complications of epidural or intrathecal anesthetic blockade. & Epidural blockade involves the risk of inadvertent dural puncture. When this occurs, cerebrospinal fluid (CSF) may leak, and a postlumbar puncture (low-pressure) headache may develop. & Rarely, the needle used for puncture may injure a nerve root. & Also rare are epidural abscesses, epidural hematoma, or injury to the cauda equina. With spinal injection, cord trauma is possible if spinal injection is made above the level of the conus.

CHAPTER 38 TEMPORARY NEURAL BLOCKADE 289 & Local anesthetics may induce temporary neuritis. & Cephalad migration of the anesthetic agent may produce an anesthetic level much higher than the level anticipated. In cervical blocks, cephalad migration may lead to respiratory arrest. & Transient hypotension is fairly common as a result of vasodilatation (sympathetic nerve block). & Intravascular injection could occur. 8. What are the indications and contraindications for epidural steroid injections? Indications for epidural steroid injections (ESIs) are still controversial. Efficacy for chronic low back pain is uncertain. In acute exacerbations of radicular nerve pain, injections may be of some benefit. Radicular pain is more likely to respond to steroid injections than is mechanical low back pain. Recovery from an acutely herniated lumbar or cervical disc may be hastened by ESIs. With acute low back pain, most clinicians use 2 to 3 weeks of conservative management before attempting ESIs. An interlaminar approach to ESI seems to be least helpful in spinal stenosis, mechanical low back pain, and long-standing, chronic low back pain. A recent study by Manchikanti and colleagues suggests that a caudal approach to epidural steroid injection is more effective for chronic low back pain than lumbar epidural. A transforaminal approach under fluoroscopic guidance is felt to sometimes help more with a far lateral disc herniation with nerve root inflammation than midline epidural. Contraindications to any epidural injection include coagulopathy, local infection, or progressive weakness that may require surgical decompression. 9. What is the appropriate timing of epidural steroid injections? A steroid formulation such as methylprednisolone or triamcinolone is usually injected in doses of 40 to 80 mg every 2 to 4 weeks to a maximum of three injections in 6 months. Evidence suggests that additional injections offer no added benefit and may increase the risk of side effects. Adrenal suppression with decreased cortisol levels has been shown to occur for 3 to 5 weeks after a typical ESI. Multiple injections may produce ligamentous laxity. 10. What are the various brachial plexus blocks? The brachial plexus can be blocked proximally at the level of the nerve roots and trunks by the interscalene approach; at the level of the divisions and cords by the supraclavicular or infraclavicular approach; and distally at the level of the terminal branches or nerves by the axillary approach. A brachial plexus block can be performed by single injection or continuous catheter technique for repeated injections or infusion. 11. For what pain conditions are brachial plexus blocks useful? Evidence for efficacy of brachial plexus blocks is anecdotal. However, some find them useful in conditions such as complex regional pain syndrome (CRPS), acute or postherpetic neuralgia involving dermatomes within vertebrae C5-T1, vascular insufficiency of Raynaud’s disease, and phantom upper limb pain. Brachial plexus block also facilitates range-of-motion (ROM) exercises in cases of frozen shoulder, elbow, or wrist. Because the thoracocervical sympathetic nerves travel in close relation to the somatic nerves of the brachial plexus, brachial plexus block results in sympathetic blockade as well. It also may be used for postoperative pain management and prevention of phantom limb pain after amputation. 12. What are the possible side effects and complications of the various brachial plexus blocks? Hematoma, neuropathy, and unintentional intravascular injection are possible with any of the brachial plexus blocks. Interscalene block may be associated with unintentional injection of local

290 CHAPTER 38 TEMPORARY NEURAL BLOCKADE anesthetic into the epidural or subarachnoid space; recurrent laryngeal nerve block, which causes hoarseness; phrenic nerve block; and ipsilateral Horner’s syndrome. Pneumothorax is most often associated with the supraclavicular block. 13. What is the sensory innervation of the lower extremities? The sciatic nerve divides at the level of the knee into the tibial and common peroneal nerves. The sural nerve, which forms from the tibial and common peroneal nerves, provides sensory innervation to the lateral aspect of the lower leg and foot. Anteriorly, the femoral nerve eventually becomes the saphenous nerve and provides sensory innervation to the medial aspect of the lower leg and foot. The lateral femoral cutaneous nerve and obturator nerve provide sensory innervation to the lateral and medial thigh, respectively. 14. What are the applications of intercostal nerve blocks? Intercostal nerve blocks are useful in acute herpetic neuralgia involving the thoracic dermatomes. Early sympathetic or neural blockade may reduce the incidence of postherpetic neuralgia. The sympathetic fibers travel with the intercostal nerves and can be blocked easily at the posterior midclavicular line, along the inferior aspect of the rib. Intercostal nerve blocks can be used to determine pain origin (differentiating between pain originating in the chest or abdominal wall and pain with a visceral origin), because the intercostal nerves innervate only the outer structures. Intercostal neuralgia and scar neuromas after thoracotomy and some cases of postherpetic neuralgia may be treated by intercostal blocks. Neurolysis by cryoanalgesia or radiofrequency lesioning may be considered if satisfactory temporary relief is obtained after local anesthetic block. 15. Describe the role of facet blockade in back pain. Facet joints may be the source of significant mechanical back and neck pain. Pain is usually deep in the paravertebral regions of the back or neck and associated with areas of referred pain. Pain resulting from facet disease increases with extension, rotation, or lateral flexion of the spine. The facet joint is innervated by the medial branch of the posterior primary ramus from the level involved and the level above. Hypertrophic arthropathy and eventually osteophytic degeneration and arthritic changes in these joints are postulated to cause the pain. Local anesthetic block of the medial branch nerve helps to make the diagnosis, although false-positive results are possible. Intraarticular or periarticular steroid injections may provide prolonged relief. Cryofrequency or radiofrequency neurolysis of the medial branch nerve is an option if local anesthetic block gives good but temporary pain relief. 16. What are the indications for a suprascapular nerve block? The suprascapular nerve not only supplies the supraspinatus muscle but also provides sensory fibers to the shoulder joint. Therefore, a suprascapular nerve block can temporarily relieve shoulder joint pain and allow the patient to perform active ROM exercises. Frozen shoulder syndrome as a result of immobilization may be prevented. When suprascapular nerve entrapment is suspected as the cause of shoulder pain, steroids also may be injected into the suprascapular notch at the superior border of the scapula. 17. When is a lateral femoral cutaneous nerve block used in chronic pain management? A lateral femoral cutaneous nerve block is sometimes useful for treatment of meralgia paresthetica, a syndrome of pain and dysesthetic cutaneous sensation in the anterolateral thigh secondary to entrapment of the lateral femoral cutaneous nerve as it passes posterior to the inguinal ligament. This syndrome is commonly associated with obesity, diabetes, or tight belts.